Organic compounds

ABSTRACT

Disclosed are δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compounds of formula (I) 
                         
and the salts thereof, having renin-inhibiting properties. Also disclosed are pharmaceutical compositions comprising these compounds and methods of administering them for the treatment of hypertension, atherosclerosis, unstable coronary syndrome, congestive heart failure, cardiac hypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstable coronary syndrome, diastolic dysfunction, chronic kidney disease, hepatic fibrosis, complications resulting from diabetes, such as nephropathy, vasculopathy and neuropathy, diseases of the coronary vessels, restenosis following angioplasty, raised intra-ocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimers, dementia, anxiety states and cognitive disorders.

This application is a 371 of PCT/EP04/13412, filed Nov. 25, 2004, whichclaims benefit of U.S. Provisional Application No. 60/525,374, filedNov. 26, 2003.

The invention relates to novel δ-amino-γ-hydroxy-ω-aryl-alkanoic acidamides of formula (I)

wherein

-   -   R¹ is hydrogen, halogen, optionally halogenated alkyl,        cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy,        lower alkoxy-lower alkoxy or free or esterified or amidated        carboxy-lower alkoxy or lower alkyl;    -   R² is hydrogen, halogen, optionally halogenated lower alkyl,        hydroxy, cycloalkyl, cycloalkoxy, optionally halogenated lower        alkoxy-lower alkyl, optionally substituted lower alkoxy-lower        alkyl, cycloalkoxy-lower alkyl; optionally lower alkanoylated,        halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower        alkyl that is unsubstituted or substituted by lower alkyl, by        lower alkanoyl and/or by lower alkoxycarbonyl, optionally        hydrogenated heteroaryl-lower alkyl, amino-lower alkoxy that is        substituted by lower alkyl, by lower alkanoyl and/or by lower        alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, lower        alkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkoxy,        lower alkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower        alkoxy-lower alkenyloxy, lower alkenyloxy-lower alkyl, lower        alkanoyl lower alkoxy, optionally S-oxidised lower        alkylthio-lower alkoxy, lower alkylthio-(hydroxy)-lower alkoxy,        aryl-lower alkoxy, aryl-lower alkyl, aryl-lower alkoxy,        optionally hydrogenated heteroaryl-lower alkoxy, optionally        hydrogenated heteroaryl-lower alkyl, cyano-lower alkoxy,        cyano-lower alkyl, free or esterified or amidated carboxy-lower        alkoxy or free or esterified or amidated carboxy-lower alkyl;    -   R³ and R⁴ are independently hydrogen, halogen, optionally        halogenated lower alkyl, hydroxy, optionally halogenated lower        alkoxy or cycloalkoxy, lower alkoxy-lower alkyl,        cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally        S-oxidised lower alkylthio-lower alkyl, optionally hydrogenated        heteroarylthio-lower alkyl, optionally hydrogenated        heteroaryl-lower alkyl; amino-lower alkyl that is unsubstituted        or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or        N-lower alkanesulfonylated or N,N-disubstituted by lower        alkylene, by unsubstituted or N′-lower alkylated or N′-lower        alkanoylated aza-lower alkylene, by oxa-lower alkylene or by        optionally S-oxidised thia-lower alkylene, cyano-lower alkyl,        free or esterified or amidated carboxy-lower alkyl, cycloalkyl,        aryl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower        alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy,        aryl-lower alkoxy, optionally halogenated lower alkoxy,        optionally S-oxidised lower alkylthio-lower alkoxy, optionally        hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated        heteroarylthio-lower alkoxy; amino-lower alkoxy that is        unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower        alkanoylated or N-lower alkanesulfonylated or substituted by        lower alkylene, by unsubstituted or N′-lower alkylated or        N′-lower alkanoylated aza-lower alkylene, by oxa-lower alkylene        or by optionally S-oxidised thia-lower alkylene, cyano-lower        alkoxy or free or esterified or amidated carboxy-lower alkoxy;        or    -   R⁴ together with R₃ is lower alkeneoxy, lower alkylenedioxy or a        fused-on aryl, optionally hydrogenated heteroaryl or cycloalkyl        ring;    -   X is methylene, hydroxymethylene, oxygen, optionally lower alkyl        substituted nitrogen, optionally oxidized sulfur,    -   R⁵ is lower alkyl or cycloalkyl;    -   R⁶ is hydrogen, lower alkyl, hydroxy, alkoxy or halogen;    -   R⁷ is unsubstituted or N-mono- or N,N-di-lower alkylated or        N-lower alkanoylated amino;    -   R⁸ is lower alkyl, lower alkenyl, cycloalkyl or aryl-lower        alkyl;    -   R⁹ is optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted cycloalkyl-alkyl, cycloalkyl        carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl        carboxamides, optionally substituted aryl-alkyl, optionally        substituted aryloxy-aryl, optionally substituted        heteroaryloxy-alkyl, free or aliphatically esterified or        etherified hydroxy-lower alkyl; amino-lower alkyl that is        unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower        alkylated or N,N-di-substituted by lower alkylene, by hydroxy-,        lower alkoxy- or lower alkanoyloxy-lower alkylene, by        unsubstituted or N′-lower alkanoylated or N′-lower alkylated        aza-lower alkylene, by oxa-lower alkylene or by optionally        S-oxidised thia-lower alkylene, free or esterified or amidated        carboxy-lower alkyl, free or esterified or amidated        dicarboxy-lower alkyl, free or esterified or amidated        carboxy-(hydroxy)lower alkyl, free or esterified or amidated        carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower        alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or        N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted        or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a        heteroaryl radical bonded via a carbon atom and optionally        hydrogenated and/or oxo-substituted, or lower alkyl substituted        by a heteroaryl radical bonded via a carbon atom and optionally        hydrogenated and/or oxo-substituted;        and to pharmaceutically acceptable salts thereof, to processes        for the preparation of the compounds according to the invention,        to pharmaceutical compositions containing them and to their use        as medicinal active ingredients.

The compounds of the present invention exhibit inhibitory activity onthe natural enzyme renin. Thus, compounds of formula (I) may be employedfor the treatment of hypertension, atherosclerosis, unstable coronarysyndrome, congestive heart failure, cardiac hypertrophy, cardiacfibrosis, cardiomyopathy postinfarction, unstable coronary syndrome,diastolic dysfunction, chronic kidney disease, hepatic fibrosis,complications resulting from diabetes, such as nephropathy, vasculopathyand neuropathy, diseases of the coronary vessels, restenosis followingangioplasty, raised intra-ocular pressure, glaucoma, abnormal vasculargrowth, hyperaldosteronism, cognitive impairment, alzheimers, dementia,anxiety states and cognitive disorders.

Listed below are definitions of various terms used to describe thecompounds of the present invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup.

Aryl and aryl in aryl-alkyl, aryl-lower alkoxy, aryl-lower alkyl and thelike is, e.g., phenyl or naphthyl that is unsubstituted or mono-, di- ortri-substituted by lower alkyl, lower alkoxy optionally substituted withhalogens, hydroxy, lower alkylamino, di-lower alkylamino, halogen and/orby trifluoromethyl.

Cycloalkoxy and cycloalkoxy in cycloalkoxy-lower alkoxy is, e.g., 3- to8-membered, preferably 3-, 5 or 6-membered, cycloalkoxy, such ascyclopropyloxy, cyclopentyloxy, cyclohexyloxy, also cyclobutyloxy,cycloheptyloxy or cyclooctyloxy.

Cycloalkyl and cycloalkyl in cycloalkyl-alkyl refers, e.g., tooptionally substituted monocyclic, bicyclic or tricyclic hydrocarbongroups of 3-12 carbon atoms, each of which may be optionally substitutedby one or more substituents such as alkenyl, alkynyl, halo, hydroxy,alkoxy, alkoxy-alkoxy, alkylthio, arylthio, aryl-alkoxy, carbamoyl,sulfamoyl, sulfonyl, -optionally substituted amino, cyano, carboxy,alkoxycarbonyl, aryl, aryloxy, heterocyclyl or alkyl optionallysubstituted by amino, halo, hydroxy, alkoxy, carboxy, carbamoyl orheterocyclyl and the like.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

Optionally substituted amino refers to a primary or secondary aminogroup which may optionally be substituted, e.g., by acyl, sulfonyl,alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,carbamoyl and the like.

Carbamoyl refers, e.g., to H₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and thelike.

Sulfamoyl refers, e.g., to H₂NS(O)₂', alkyl-NHS(O)₂—, (alkyl)₂NS(O)₂—,aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—, (aryl)₂NS(O)₂—, heteroaryl-NHS(O)₂—,aralkyl-NHS(O)₂—, heteroaralkyl-NHS(O)₂— and the like.

Free or esterified or amidated carboxy-lower alkoxy is, e.g.,carboxy-lower alkoxy, lower alkoxycarbonyl-lower alkoxy, carbamoyl-loweralkoxy or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkoxy.

Optionally substituted lower alkanoylated, halogenated or sulfonylatedhydroxy-lower alkoxy is, e.g., lower alkanoyloxy-lower alkyl,hydroxy-lower alkoxy, halo-(hydroxy)-lower alkoxy or loweralkanesulfonyl-(hydroxy)lower alkoxy.

Amino-lower alkyl that is unsubstituted or substituted by lower alkyl,lower alkanoyl and/or by lower alkoxycarbonyl is, e.g., amino-loweralkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl,lower alkanoylamino-lower alkyl or lower alkoxycarbonylamino-loweralkyl.

Amino-lower alkoxy that is unsubstituted or substituted by lower alkyl,lower alkanoyl and/or by lower alkoxycarbonyl is, e.g., amino-loweralkoxy, lower alkylamino-lower alkoxy, di-lower alkylamino-lower alkoxy,lower alkanoylamino-lower alkoxy or lower alkoxycarbonylamino-loweralkoxy.

Optionally S-oxidised lower alkylthio-lower alkoxy is, e.g., loweralkylthio-lower alkoxy, or lower alkanesulfonyl-lower alkoxy.

Optionally hydrogenated heteroaryl-lower alkoxy is, e.g., optionallypartially hydrogenated or N-oxidised pyridyl-lower alkoxy,thiazolyl-lower alkoxy or especially morpholino-lower alkoxy.

Optionally hydrogenated heteroarylthio-lower alkoxy is, e.g., optionallypartially or fully hydrogenareal heteroarylthio-lower alkoxy, such asthiazolylthio-lower alkoxy or thiazolinylthio-lower alkoxy,imidazolylthio-lower alkoxy, optionally N-oxidised pyridlylthio-loweralkoxy or pyrimidinylthio-lower alkoxy.

Free or esterified or amidated carboxy-lower alkyl is, e.g.,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-loweralkyl or N-mono- or N,N-di-lower alkylcarbamoyl-lower alkyl.

Optionally halogenated lower alkyl is, e.g., lower alkyl orpolyhalo-lower alkyl.

Optionally halogenated lower alkoxy is, e.g., lower alkoxy orpolyhalo-lower alkoxy.

Optionally S-oxidised lower alkylthio-lower alkyl is, e.g., loweralkylthio-lower alkyl or lower alkanesulfonyl-lower alkyl.

Optionally S-oxidised lower alkylthio-lower alkoxy is, e.g., loweralkylthio-lower alkoxy or lower alkanesulfonyl-lower alkoxy.

Optionally hydrogenated heteroaryl-lower alkyl is, e.g., optionallypartially hydrogenated or N-oxidised pyridyl-lower alkyl.

Optionally hydrogenated heteroarylthio-lower alkyl is, e.g.,thiazolylthio-lower alkyl or thiazolinylthio-lower alkyl,imidazolylthio-lower alkyl, optionally N-oxidised pyridylthio-loweralkyl or pyrimidinylthio-lower alkyl.

Amino-lower alkyl that is unsubstituted or N-mono- or N,N-di-loweralkylated, N-lower alkanoylated or N-lower alkanesulfonylated orN,N-disubstituted by lower alkylene, by unsubstituted or N′-loweralkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-loweralkylene; or by optionally S-oxidised thia-lower alkylene is, e.g.,amino-lower alkyl, lower alkylamino-lower alkyl, di-loweralkylamino-lower alkyl, lower alkanoylamino-lower alkyl, loweralkanesulfonylamino-lower alkyl, polyhalo-loweralkanesulfonylamino-lower alkyl, pyrrolidino-lower alkyl,piperidino-lower alkyl, piperazino-, N′-lower alkylpiperazino- orN′-lower alkanoylpiperazino-lower alkyl, morpholino-lower alkyl,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothiomorpholino-loweralkyl.

Optionally S-oxidised lower alkylthio-lower alkoxy is, e.g., loweralkylthio-lower alkoxy or lower alkanesulfonyl-lower alkoxy.

Amino-lower alkoxy that is unsubstituted or N-mono- or N,N-di-loweralkylated, N-lower alkanoylated or N-lower alkanesulfonylated orN,N-disubstituted by lower alkylene, by unsubstituted or N′-loweralkylated or N′-lower alkanoylated aza-lower alkylene, by oxa-loweralkylene or by optionally S-oxidised thia-lower alkylene is, e.g.,amino-lower alkoxy, lower alkylamino-lower alkoxy, di-loweralkylamino-lower alkoxy, lower alkanoylamino-lower alkoxy, loweralkanesulfonylamino-lower alkoxy, polyhalo-loweralkanesulfonylamino-lower alkoxy, pyrrolidino-lower alkoxy,piperidino-lower alkoxy, piperazino-, N′-lower alkylpiperazino- orN′-lower alkanoylpiperazino-lower alkoxy, morpholino-lower alkoxy,thiomorpholino-, S-oxothiomorpholino- or S,S-dioxothio-morpholino-loweralkoxy.

Unsubstituted or N-mono- or N,N-di-lower alkylated or N-loweralkanoylated amino is, e.g., amino, lower alkylamino, di-loweralkylamino or lower alkanoylamino.

Free or aliphatically esterified or etherified hydroxy-lower alkyl is,e.g., hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, loweralkoxy-lower alkyl or lower alkenyloxy-lower alkyl.

Amino-lower alkyl that is unsubstituted or N-lower alkanoylated, N-mono-or N,N-di-lower alkylated or N,N-disubstituted by lower alkylene, byhydroxy-, lower alkoxy- or lower alkanoyloxy-lower alkylene, byunsubstituted or N′-lower alkanoylated aza-lower alkylene, by oxa-loweralkylene; or by optionally S-oxidised thia-lower alkylene is, e.g.,amino-lower alkyl, lower alkanoylamino-lower alkyl, N-mono- orN,N-di-lower alkylamino-lower alkyl, optionally hydroxylated or loweralkoxylated piperidino-lower alkyl, such as piperidino-lower alkyl,hydroxypiperidino-lower alkyl or lower alkoxy-piperidino-lower alkyl,piperazino-, W-lower alkylpiperazino-; or N′-loweralkanoyl-piperazino-lower alkyl, unsubstituted or lower alkylatedmorpholino-lower alkyl, such as morpholino-lower alkyl ordimethylmorpholino-lower alkyl; or optionally S-oxidisedthio-morpholino-lower alkyl, such as thiomorpholino-lower alkyl orS,S-dioxothiomorpholino-lower alkyl.

Free or esterified or amidated dicarboxy-lower alkyl is, e.g.,dicarboxy-lower alkyl, di-lower alkoxycarbonyl-lower alkyl,dicarbamoyl-lower alkyl or di-(N-mono- or N,N-di-loweralkylcarbamoyl)-lower alkyl.

Free or esterified or amidated carboxy-(hydroxy)lower alkyl is, e.g.,carboxy-(hydroxy)-lower alkyl, lower alkoxycarbonyl-(hydroxy)-loweralkyl or carbamoyl-(hydroxy)-lower alkyl.

Free or esterified or amidated carboxycycloalkyl-lower alkyl is, e.g.,5- or 6-membered carboxycycloalkyl-lower alkyl, loweralkoxycarbonylcycloalkyl-lower alkyl, carbamoylcycloalkyl-lower alkyl orN-mono- or N,N-di-lower alkylcarbamoylcyclo-alkyl-lower alkyl.

Unsubstituted or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkylis, e.g., sulfamoyl-lower alkyl, lower alkylsulfamoyl-lower alkyl ordi-lower alkyl-sulfamoyl-lower alkyl.

Unsubstituted or N-mono- or N,N-di-lower alkylated thiocarbamoyl-loweralkyl is, e.g., thiocarbamoyl-lower alkyl, loweralkylthiocarbamoyl-lower alkyl; or di-lower alkylthiocarbamoyl-loweralkyl, such as N,N-dimethylthiocarbamoylmethyl.

Hereinbefore and hereinafter, lower radicals and compounds are to beunderstood as being, e.g., those having up to and including 7 carbonatoms, preferably up to and including 4 carbon atoms.

Five- or 6-membered carboxycycloalkyl-lower alkyl, loweralkoxycarbonylcycloalkyl-lower alkyl, carbamoylcycloalkyl-lower alkyl,N-mono- or N,N-di-lower alkylcarbamoylcyclo-alkyl-lower alkyl is, e.g.,ω-(1-carboxycycloalkyl)-C₁-C₄alkyl, ω-(1-loweralkoxycarbonylcycloalkyl)C₁-C₄alkyl,ω-(1-carbamoylcycloalkyl)-C₁-C₄alkyl, ω-(1-loweralkylcarbamoylcycloalkyl)-C₁-C₄alkyl or ω-(1-di-loweralkylcarbamoylcycloalkyl)-C₁-C₄alkyl, wherein cycloalkyl is, e.g.,cyclopentyl or cyclohexyl; lower alkoxycarbonyl is, e.g.,C₁-C₄alkoxycarbonyl, such as methoxy- or ethoxycarbonyl; loweralkylcarbamoyl is, e.g., C₁-C₄alkylcarbamoyl, such as methylcarbamoyl;di-lower alkylcarbamoyl is, e.g., di-C₁-C₄alkylcarbamoyl, such asdimethylcarbamoyl; and lower alkyl is, e.g., C₁-C₄alkyl, such as methyl,ethyl, propyl or butyl, especially (1-carboxycyclopentyl)methyl.

Five- or 6-membered cycloalkoxy-lower alkoxy is, e.g., cyclopentyloxy-or cyclohexyloxy-C₁-C₄alkoxy, such as cyclopentyloxy- orcyclohexyloxy-methoxy, 2-cyclopentyloxy- or 2-cyclohexyloxy-ethoxy, 2-or 3-cyclopentyloxy- or 2- or 3cyclohexyloxy-propyloxy or4-cyclopentyloxy- or 4-cyclohexyloxy-butyloxy, especiallycyclopentyloxy- or cyclohexyloxy-methoxy.

Five- or 6-membered cycloalkoxy-lower alkyl is, e.g., cyclopentyloxy- orcyclohexyloxy-C₁-C₄alkyl, such as cyclopentyloxy- orcyclohexyloxy-methyl, 2-cyclopentyloxy- or 2-cyclohexyloxy-ethyl, 2- or3-cyclopentyloxy- or 2- or 3-cyclohexyloxy-propyl, 2-cyclopentyloxy- or2-cyclohexyloxy-2-methyl-propyl, 2-cyclopentyloxy- or2-cyclohexyloxy-2-ethyl-butyl or 4-cyclopentyloxy- or4cyclohexyloxy-butyl, especially cyclopentyloxy- orcyclohexyloxy-methyl.

Amino-lower alkoxy is, e.g., amino-C₁-C₄alkoxy, such as 2-aminoethoxy or5-aminopentyloxy, also 3-aminopropyloxy or 4-aminobutyloxy.

Amino-lower alkyl is, e.g., amino-C₁-C₄alkyl, such as 2-aminoethyl,3-aminopropyl or 4-aminobutyl.

Carbamoyl-(hydroxy)-lower alkyl is, e.g., carbamoyl-C₁-C₇(hydroxy)alkyl,such as 1-carbamoyl-2-hydroxyethyl.

Carbamoyl-lower alkoxy is, e.g., carbamoyl-C₁-C₄alkoxy, such ascarbamoylmethoxy, 2-carbamoylethoxy, 3-carbamoylpropyloxy or4-carbamoylbutyloxy, especially carbamoylmethoxy.

Carbamoyl-lower alkyl is, e.g., carbamoyl-C₁-C₇alkyl, such ascarbamoylmethyl, 2-carbamoylethyl, 3-carbamoylpropyl,2-(3-carbamoyl)propyl, 2-carbamoylpropyl, 3-(1-carbamoyl)propyl,2-(2-carbamoyl)propyl, 2-(carbamoyl-2-methyl)propyl, 4-carbamoylbutyl,1-carbamoylbutyl, 1-(1-carbamoyl-2-methyl)butyl or3-(4-carbamoyl-2-methyl)butyl.

Carboxy-(hydroxy)-lower alkyl is, e.g., carboxy-C₁-C₇(hydroxy)alkyl,such as 1-carboxy-2-hydroxy-ethyl.

Carboxy-lower alkoxy is, e.g., carboxy-C₁-C₄alkoxy, such ascarboxymethoxy, 2-carboxyethoxy, 2- or 3-carboxypropyloxy or4-carboxybutyloxy, especially carboxy-methoxy.

Carboxy-lower alkyl is, e.g., carboxy-C₁-C₄alkyl, such as carboxymethyl,2-carboxyethyl, 2- or 3-carboxypropyl, 2-carboxy-2-methyl-propyl,2-carboxy-2-ethyl-butyl or 4-carboxybutyl, especially carboxymethyl.

Cyano-lower alkoxy is, e.g., cyano-C₁-C₄alkoxy, such as cyanomethoxy,2-cyano-ethoxy, 2- or 3-cyanopropyloxy or 4-cyanobutyloxy, especiallycyanomethoxy.

Cyano-lower alkyl is, e.g., cyano-C₁-C₄alkyl, such as cyanomethyl,2-cyanoethyl, 2- or 3-cyanopropyl, 2-cyano-2-methyl-propyl,2-cyano-2-ethyl-butyl or 4-cyanobutyl, especially cyanomethyl.

Di-(N-mono- or N,N-di-lower alkylcarbamoyl)-lower alkyl is, e.g.,di-(N-mono- or N,N-di-C₁-C₄alkylcarbamoyl)-C₁-C₄alkyl, such as1,2-di-(N-mono- or N,N-di-C₁-C₄alkylcarbamoyl)ethyl or 1,3-di-(N-mono-or N,N-di-C₁-C₄alkylcarbamoyl)propyl.

Dicarbamoyl-lower alkyl is, e.g., dicarbamoyl-C₁-C₄alkyl, such as1,2-dicarbamoylethyl or 1,3-dicarbamoylpropyl.

Dicarboxy-lower alkyl is, e.g., dicarboxy-C₁-C₄alkyl, such as1,2-dicarboxyethyl or 1,3-dicarboxypropyl.

Dimethylmorpholino-lower alkoxy can be N-oxidised and is, e.g.,2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-C₁-C₄alkoxy, such as2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-methoxy,2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-ethoxy,3-(2,6-dimethylmorpholino-or 3,5-dimethylmorpholino)-propyloxy,2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino3-methyl)propyloxy,or 1- or 2-[4-(2,6-dimethylmorpholino- or3,5-dimethylmorpholino)]-butyloxy.

Dimethylmorpholino-lower alkyl can be N-oxidised and is, e.g.,2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-C₁-C₄alkyl, such as2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-methoxy,2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-ethoxy,3-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino)-propyl,2-(2,6-dimethylmorpholino- or 3,5-dimethylmorpholino-3-methyl)-propyl,or 1- or 2-[4-(2,6-dimethylmorpholino- or3,5-dimethylmorpholino)]-butyl.

Di-lower alkoxycarbonyl-lower alkyl is, e.g., di-loweralkoxycarbonyl-C₁-C₄alkyl, such as 1,2-dimethoxycarbonylethyl,1,3-dimethoxycarbonylpropyl, 1,2-dimethoxycarbonylethyl or1,3-diethoxycarbonylpropyl.

Di-lower alkylamino is, e.g., di-C₁-C₄alkylamino, such as dimethylamino,N-methyl-N-ethylamino, diethylamino, N-methyl-N-propylamino orN-butyl-N-methylamino.

Di-lower alkylamino-lower alkoxy is, e.g.,N,N-di-C₁-C₄alkylamino-C₁-C₄alkoxy, such as 2-dimethylaminoethoxy,3-dimethylaminopropyloxy, 4-dimethylaminobutyloxy, 2-diethylaminoethoxy,2-(N-methyl-N-ethyl-amino)ethoxy or 2-(N-butyl-N-methyl-amino)ethoxy.

Di-lower alkylamino-lower alkyl is, e.g.,N,N-di-C₁-C₄alkylamino-C₁-C₄alkyl, such as 2-dimethylaminoethyl,3-dimethylaminopropyl, 4-dimethylaminobutyl, 2-diethylaminoethyl,2-(N-methyl-N-ethyl-amino)ethyl or 2-(N-butyl-N-methyl-amino)ethyl.

Di-lower alkylcarbamoyl-lower alkoxy is, e.g.,N,N-di-C₁-C₄alkylcarbamoyl-C₁-C₄alkoxy, such as methyl- ordimethyl-carbamoyl-C₁-C₄alkoxy, such as N-methyl-, N-butyl- orN,N-dimethyl-carbamoylmethoxy, 2-(N-methylcarbamoyl)ethoxy,2-(N-butylcarbamoyl)ethoxy, 2-(N,N-dimethylcarbamoyl)ethoxy,3-(N-methylcarbamoyl)propyloxy, 3-(N-butylcarbamoyl)propyloxy,3-(N,N-dimethylcarbamoyl)propyloxy or 4-(N-methylcarbamoyl)butyloxy,4-(N-butylcarbamoyl)butyloxy or 4-(N,N-dimethylcarbamoyl)butyloxy,especially N-methyl-, N-butyl- or N,N-dimethyl-carbamoylmethoxy.

Di-lower alkylcarbamoyl-lower alkyl is, e.g.,N,N-di-C₁-C₄alkylcarbamoyl-C₁-C₄alkyl, such as 2-dimethylcarbamoylethyl,3-dimethylcarbamoylpropyl, 2-dimethylcarbamoylpropyl,2-(dimethylcarbamoyl-2-methyl)propyl or2-(1-dimethylcarbamoyl-3-methyl)butyl.

Di-lower alkylsulfamoyl-lower alkyl is, e.g.,N,N-di-C₁-C₄alkylsulfamoyl-C₁-C₄alkyl, N,N-dimethylsulfamoyl-C₁-C₄alkyl,such as N,N-dimethylsulfamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl,3-(N,N-dimethylcarbamoyl)propyl or 4-(N,N-dimethylcarbamoyl)butyl,especially N,N-dimethylcarbamoylmethyl.

Unsubstituted or N-lower alkanoylated piperidyl-lower alkyl is, e.g.,1-C₁-C₇lower alkanoylpiperidin-4-yl-C₁-C₄alkyl, such as1-acetylpiperidinylmethyl or 2-(1-acetylpiperidinyl)ethyl.

Optionally partially hydrogenated or N-oxidised pyridyl-lower alkoxy is,e.g., optionally partially hydrogenated pyridyl- orN-oxidopyridyl-C₁-C₄alkoxy, such as pyridyl- or N-oxidopyridyl-methoxy,2-pyridylethoxy, 2- or 3-pyridylpropyloxy or 4-pyridylbutyloxy,especially 3- or 4-pyridylmethoxy.

Optionally partially hydrogenated or N-oxidised pyridyl-lower alkyl is,e.g., optionally partially hydrogenated pyridyl- orN-oxidopyridyl-C₁-C₄alkyl, such as pyridyl- or N-oxidopyridyl-methyl,2-pyridylethyl, 2- or 3-pyridylpropyl or 4-pyridylbutyl, especially 3-or 4-pyridylmethyl.

Halo-(hydroxy)-lower alkoxy is, e.g., halo-C₂-C₇(hydroxy)alkoxy,especially halo-C₂-C₄(hydroxy)alkoxy, such as 3-halo-, such as3-chloro-2-hydroxy-propyloxy.

Hydroxy-lower alkoxy is, e.g., hydroxy-C₂-C₇alkoxy, especiallyhydroxy-C₂-C₄alkoxy, such as 2-hydroxybutyloxy, 3-hydroxypropyloxy or4-hydroxybutyloxy.

Hydroxy-lower alkyl is, e.g., hydroxy-C₂-C₇alkyl, especiallyhydroxy-C₂-C₄alkyl, such as 2-hydroxyethyl, 3-hydroxypropyl or4-hydroxybutyl.

Hydroxypiperidino-lower alkyl is, e.g., 3- or4-hydroxypiperidino-C₁-C₄alkoxy, such as 3- or4-hydroxypiperidinomethoxy, 2-(3- or 4-hydroxypiperidino)ethoxy, 3-(3-or 4-hydroxypiperidino)propyloxy or 4-(3- or4-hydroxypiperidino)butyloxy.

Imidazolyl-lower alkyl is, e.g., imidazolyl-C₁-C₄alkyl, such asimidazol4-yl-methyl, 2-(imidazol4-yl)ethyl, 3-(imidazol-4-yl)propyl or4-(imidazol-4-yl)butyl.

Imidazolyl-lower alkoxy is, e.g., imidazolyl-C₁-C₄alkoxy, such asimidazol-4-yl-methoxy, 2-(imidazol4-yl)ethoxy, 3-(imidazol4-yl)propyloxyor 4-(imidazol4-yl)butyloxy.

Imidazolyl-lower alkyl is, e.g., imidazolyl-C₁-C₄alkyl, such asimidazol-4-yl-methyl, 2-(imidazol4-yl)ethyl, 3-(imidazol4-yl)propyl or4-(imidazol-4-yl)butyl.

Morpholinocarbonyl-lower alkyl is, e.g., morpholinocarbonyl-C₁-C₄alkyl,such as 1-morpholinocarbonylethyl, 3-morpholinocarbonylpropyl or1-(morpholinocarbonyl-2-methyl)propyl.

Morpholino-lower alkoxy can be N-oxidised and is, e.g.,morpholino-C₁-C₄alkoxy, such as 1-morpholinoethoxy,3-morpholinopropyloxy or 1-(morpholino-2-methyl)propyloxy.

Morpholino-lower alkyl can be N-oxidised and is, e.g.,morpholino-C₁-C₄alkyl, such as morpholinomethyl, 2-morpholinoethyl,3-morpholinopropyl or 1- or 2-(4-morpholino)butyl.

Lower alkanoyl is, e.g., C₁-C₇alkanoyl, especially C₂-C₆alkanoyl, suchas acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoylamino is, e.g., N-C₁-C₇alkanoylamino, such as acetylaminoor pivaloylamino.

Lower alkanoylamino is, e.g., N-C₁-C₇alkanoylamino, such as acetylaminoor pivaloylamino.

Lower alkanoylamino-lower alkyl is, e.g.,N-C₁-C₄alkanoylamino-C₁-C₄alkyl, such as 2-acetoxyaminoethyl.

Lower alkanoylamino-lower alkyl is, e.g.,N-C₁-C₄alkanoylamino-C₁-C₄alkyl, such as 2-acetoxyaminoethyl.

Lower alkanoyl-lower alkoxy (oxo-lower alkoxy) carries the loweralkanoyl group in a position higher than the α-position and is, e.g.,C₁-C₇alkanoyl-C₁-C₄alkoxy, such as 4-acetylbutoxy.

Lower alkanoyloxy-lower alkyl carries the lower alkanoyloxy group in aposition higher than the α-position and is, e.g.,C₁-C₇alkanoyloxy-C₁-C₄alkyl, such as 4-acetoxy-butyl.

Lower alkanesulfonyl-(hydroxy)-lower alkoxy is, e.g.,C₁-C₇alkanesulfonyl-C₁-C₄(hydroxy)alkoxy, such as3-methanesulfonyl-2-hydroxy-propyloxy.

Lower alkanesulfonyl-lower alkoxy is, e.g.,C₁-C₇alkanesulfonyl-C₁-C₄alkoxy, such as methanesulfonylmethoxy or3methanesulfonyl-2-hydroxy-propyloxy.

Lower alkanesulfonylamino-lower alkoxy is, e.g.,C₁-C₇alkanesulfonylamino-C₁-C₄alkoxy, such asethanesulfonylaminomethoxy, 2-ethanesulfonylaminoethoxy,3-ethanesulfonylaminopropyloxy or3-(1,1-dimethylethanesulfonylamino)propyloxy.

Lower alkanesulfonylamino-lower alkyl is, e.g.,C₁-C₇alkanesulfonylamino-C₁-C₄alkyl, such as ethanesulfonylaminomethyl,2-ethanesulfonylaminoethyl, 3-ethanesulfonylaminopropyl or3-(1,1-dimethylethanesulfonylamino)propyl.

Lower alkanesulfonyl-lower alkyl is, e.g.,C₁-C₇alkanesulfonyl-C₁-C₄alkyl, such as ethanesulfonylmethyl,2-ethanesulfonylethyl, 3-ethanesulfonylpropyl or3-(1,1-dimethylethanesulfonyl)propyl.

Lower alkenyl is, e.g., C₁-C₇alkenyl, such as vinyl or allyl.

Lower alkenyloxy is, e.g., C₁-C₇alkenyloxy, such as allyloxy.

Lower alkenyloxy-lower alkoxy is, e.g., C₁-C₇alkenyloxy-C₁-C₄alkoxy,such as allyloxymethoxy.

Lower alkenyloxy-lower alkyl is, e.g., C₁-C₇alkenyloxy-C₁-C₄alkyl, suchas allyloxymethyl.

Lower alkoxy is, e.g., C₁-C₇alkoxy, preferably C₁-C₅alkoxy, such asmethoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,secondary butyloxy, tertiary butyloxy, pentyloxy or a hexyloxy orheptyloxy group.

Lower alkoxycarbonyl is, e.g., C₁-C₇alkoxycarbonyl, preferablyC₁-C₅alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl,isobutyloxycarbonyl, secondary butyloxycarbonyl, tertiary butyloxy,pentyloxycarbonyl or a hexyloxycarbonyl or heptyloxycarbonyl group.

Lower alkoxycarbonyl-(hydroxy)-lower alkyl is, e.g.,C₁-C₄alkoxycarbonyl-C₁-C₇(hydroxy)alkyl, such as 1-methoxycarbonyl- or1-ethoxycarbonyl-2-hydroxy-ethyl.

Lower alkoxycarbonylamino-lower alkoxy is, e.g.,C₁-C₇alkoxycarbonylamino-C₂-C₇alkoxy, preferablyC₂-C₅alkoxycarbonylamino-C₂-C₇alkoxy, such asmethoxycarbonylamino-C₂-C₇alkoxy, ethoxycarbonylamino-C₂-C₇alkoxy,propyloxycarbonylamino-C₂-C₇alkoxy,isobutyloxycarbonylamino-C₂-C₇alkoxy, butyloxycarbonylamino-C₂-C₇alkoxy,isobutyloxycarbonylamino-C₂-C₇alkoxy, secondarybutyloxycarbonylamino-C₂-C₇alkoxy or tertiary butyloxyamino-C₂-C₇alkoxy,wherein C₂-C₇alkoxy is, e.g., methoxy, ethoxy, propyloxy, butyloxy,pentyloxy or hexyloxy.

Lower alkoxycarbonylamino-lower alkyl is, e.g.,C₁-C₇alkoxycarbonylamino-C₂-C₇alkyl, preferablyC₂-C₅alkoxycarbonylamino-C₂-C₇alkyl, such as methoxycarbonyl-C₂-C₇alkyl,ethoxycarbonylamino-C₂-C₇alkyl, propyloxycarbonylamino-C₂-C₇alkylisopropyloxycarbonylamino-C₂-C₇alkyl, butyloxycarbonylamino-C₂-C₇alkyl,isobutyloxycarbonylamino-C₂-C₇alkyl, secondarybutyloxycarbonylamino-C₂-C₇alkyl or tertiary butyloxyamino-C₂-C₇alkyl,wherein C₂-C₇alkyl is, e.g., methyl, ethyl, propyl, butyl, pentyl orhexyl.

Lower alkoxycarbonyl-lower alkoxy is, e.g.,C₁-C₄alkoxycarbonyl-C₁-C₄alkoxy, such as methoxycarbonyl- orethoxycarbonyl-methoxy, 2-methoxycarbonyl- or 2-ethoxycarbonyl-ethoxy,2- or 3-methoxycarbonyl- or 2- or 3-ethoxycarbonyl-propyloxy or4-methoxycarbonyl- or 4-ethoxycarbonyl-butyloxy, especiallymethoxycarbonyl- or ethoxycarbonyl-methoxy or 3-methoxycarbonyl- or3-ethoxycarbonyl-propyloxy.

Lower alkoxycarbonyl-lower alkyl is, e.g.,C₁-C₄alkoxycarbonyl-C₁-C₄alkyl, such as methoxycarbonyl- orethoxycarbonyl-methoxy, 2-methoxycarbonyl- or 2-ethoxycarbonyl-ethoxy,3-methoxycarbonyl- or 3-ethoxycarbonyl-propyloxy or4-ethoxycarbonylbutyloxy.

Lower alkoxy-lower alkenyl is, e.g., C₁-C₄alkoxy-C₂-C₄alkenyl, such as4-methoxybut-2-enyl.

Lower alkoxy-lower alkoxy is, e.g., C₁-C₄alkoxy-C₂-C₄alkoxy, such as2-methoxy-, 2-ethoxy- or 2-propyloxy-ethoxy, 3-methoxy- or3-ethoxy-propyloxy or 4-methoxybutyloxy, especially 3-methoxypropyloxyor 4-methoxybutyloxy.

Lower alkoxy-lower alkoxy-lower alkyl is, e.g.,C₁-C₄alkoxy-C₁-C₄alkoxy-C₁-C₄alkyl, such as 2-methoxy-, 2-ethoxy- or2-propyloxy-ethoxymethyl, 2-(2-methoxy-, 2-ethoxy- or2-propyloxy-ethoxy)ethyl, 3-(3-methoxy- or 3-ethoxy-propyloxy)propyl or4-(2-methoxybutyloxy)butyl, especially 2-(3-methoxypropyloxy)ethyl or2-(4-methoxybutyloxy)ethyl.

Lower alkoxy-lower alkyl is, e.g., C₁-C₄alkoxy-C₁-C₄alkyl, such asethoxymethyl, propyloxymethyl, butyloxymethyl, 2-methoxy-, 2-ethoxy- or2-propyloxy-ethyl, 3-methoxy- or 3-ethoxy-propyl or 4-methoxybutyl,especially 3-methoxypropyl or 4-methoxybutyl.

Lower alkoxypiperidino-lower alkyl is, e.g., piperidino-,hydroxypiperidino- or lower alkoxypiperidino-C₁-C₄alkyl, such aspiperidinomethyl, 4-hydroxypiperidinomethyl or 4-C₁-C₄alkoxy-, such as4-methoxy-piperidinomethyl.

Lower alkoxypiperidino-lower alkyl is, e.g.,C₁-C₄alkoxypiperidino-C₁-C₄alkyl, such as4-C₁-C₄alkoxy-piperidinomethyl, especially 4-methoxypiperidinomethyl.

Lower alkyl may be straight-chained or branched and/or bridged and is,e.g., corresponding C₁-C₇alkyl, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, or apentyl, hexyl or heptyl group. Lower alkyl R₂ or R₃ is especiallyC₂-C₇alkyl, lower alkyl R₅ or R₇ is especially branched C₃-C₇alkyl andlower alkyl R₈ or R₃ is, e.g., straight-chained, branched or bridgedC₃-C₇alkyl.

Lower alkylamino is, e.g., C₁-C₄alkylamino, such as methylamino,ethylamino, propylamino, butylamino, isobutylamino, secondary butylaminoor tertiary butylamino.

Lower alkylamino-lower alkoxy is, e.g., C₁-C₄alkylamino-C₁-C₄alkoxy,such as propylaminomethoxy, 2-methylamino-, 2-ethylamino-,2-propylamino- or 2-butylamino-ethoxy, 3-ethylamino- or3-propylamino-propyloxy or 4-methylaminobutoxy.

Lower alkylamino-lower alkyl is, e.g., C₁-C₄alkylamino-C₁-C₄alkyl, suchas propylaminomethyl, 2-methylamino-, 2-ethylamino-, 2-propylamino- or2-butylamino-ethyl, 3-ethylamino- or 3-propylamino-propyl or4-methylaminobutyl.

Lower alkylcarbamoyl-lower alkoxy is, e.g.,N-C₁-C₇alkylcarbamoyl-C₁-C₄alkoxy, such as methyl- ordimethyl-carbamoyl-C₁-C₄alkoxy, e.g. methylcarbamoylmethoxy,2-methylcarbamoylethoxy or 3-methylcarbamoylpropyloxy.

Lower alkylenedioxy is, e.g., methylenedioxy or ethylenedioxy, but canalso be 1,3- or 1,2-propylenedioxy.

Lower alkylsulfamoyl-lower alkyl is, e.g.,N-C₁-C₇alkylsulfamoyl-C₁-C₄alkyl, such as N-methyl-, N-ethyl-, N-propyl-or N-butyl-sulfamoyl-C₁-C₄alkyl, such as N-methyl-, N-ethyl-, N-propyl-or N-butyl-sulfamoylmethyl, 2-(N-methylsulfamoyl)ethyl,2-(N-butylsulfamoyl)ethyl, 3-(N-methylsulfamoyl)propyl,3-(N-butylsulfamoyl)propyl or 4-(N-methylsulfamoyl)butyl,4-(N-butylsulfamoyl)butyl or 4-(N,N-dimethylsulfamoyl)butyl, especiallyN-methyl-, N-butyl- or N,N-dimethyl-sulfamoylmethyl.

Lower alkylthio-(hydroxy)-lower alkoxy is, e.g.,N-C₁-C₄alkylthio-C₁-C₄(hydroxy)alkoxy, such as2-hydroxy-3-methylthiopropyloxy.

Oxazolyl-lower alkyl is, e.g., oxazolyl-C₁-C₄alkyl, such as2-(1,2,4-oxadiazol-5-yl)ethyl, 3(1,2,4-oxadiazol-5-yl)propyl or4-(1,2,4-oxadiazol-5-yl)butyl.

Lower alkylthio-lower alkoxy is, e.g., N-C₁-C₄alkylthio-C₁-C₄alkoxy,such as methylthio-C₁-C₄alkoxy, e.g., methylthiomethoxy,2-methylthioethoxy or 3-methylthiopropyloxy.

Lower alkylthio-lower alkyl is, e.g., N-C₁-C₄alkylthio-C₁-C₄alkyl, suchas methylthio-C₁-C₄alkyl, e.g., methylthiomethyl, 2-methylthioethyl or3-methylthiopropyl.

N′-Lower alkanoylpiperazino-lower alkoxy is, e.g., N′-loweralkanoylpiperazino-C₁-C₄alkoxy, such as 4-acetylpiperazinomethoxy.

N′-Lower alkanoylpiperazino-lower alkyl is, e.g., N′-C₂-C₇-loweralkanoylpiperazino-C₁-C₄alkyl, such as 4-acetylpiperazinomethyl.

N′-Lower alkylpiperazino-lower alkyl is, e.g.,N′-C₁-C₄alkylpiperazino-C₁-C₄alkyl, such as 4-methylpiperazinomethyl.

Oxo-lower alkoxy is, e.g., oxo-C₁-C₄alkoxy, such as3,3-dimethyl-2-oxo-butyloxy.

Piperazino-lower alkyl is, e.g., piperazino-C₁-C₄alkyl, such aspiperazinomethyl, 2-piperazinoethyl or 3-piperazinopropyl.

Piperidino-lower alkoxy is, e.g., piperidino-C₁-C₄alkoxy, such aspiperidinomethoxy, 2-piperidinoethoxy or 3-piperidinopropyloxy.

Piperidino-lower alkyl is, e.g., piperidino-C₁-C₄alkyl, such aspiperidinomethyl, 2-piperidinoethyl or 3-piperidinopropyl.

Polyhalo-lower alkanesulfonylamino-lower alkoxy is, e.g.,trifluoro-C₁-C₇alkanesulfonyl-C₁-C₄alkoxy, such astrifluoromethanesulfonylaminobutyloxy.

Polyhalo-lower alkanesulfonylamino-lower alkyl is, e.g.,trifluoro-C₁-C₇alkanesulfonyl-C₁-C₄alkyl, such astrifluoromethanesulfonylaminobutyl.

Pyrimidinyl-lower alkoxy is, e.g., pyrimidinyl-C₁-C₄alkoxy, such aspyrimidinylmethoxy, 2-pyrimidinylethoxy or 3-pyrimidinylpropyloxy.

Pyrimidinyl-lower alkyl is, e.g., pyrimidinyl-C₁-C₄alkyl, such aspyrimidinylmethyl, 2-pyrimidinylethyl or 3-pyrirnidinylpropyl.

Pyrrolidino-lower alkoxy is, e.g., pyrrolidino-C₂-C₄alkoxy, such as2-pyrrolidinoethoxy or 3-pyrrolidinopropyloxy.

Pyrrolidino-lower alkyl is, e.g., pyrrolidino-C₁-C₄alkyl, such aspyrrolidinomethyl, 2-pyrrolidinoethyl or 3-pyrrolidinopropyl.

S,S-Dioxothiomorpholino-lower alkyl is, e.g.,S,S-dioxothiomorpholino-C₁-C₄alkyl, such asS,S-dioxothiomorpholinomethyl or 2-(S,S-dioxo)thiomorpholinoethyl.

S-Oxothiomorpholino-lower alkyl is, e.g.,S-oxothiomorpholino-C₁-C₄alkyl, such as S-oxothiomorpholinomethyl or2-(S-oxo)thiomorpholinoethyl.

Sulfamoyl-lower alkyl is, e.g., sulfamoyl-C₁-C₄alkyl, such assulfamoyl-C₁-C₄alkyl, such as sulfamoylmethyl, 2-sulfamoylethyl,3-sulfamoylpropyl or 4-sulfamoylbutyl.

Tetrazolyl-lower alkyl is, e.g., tetrazolyl-C₁-C₄alkyl, such astetrazol-5-ylmethyl, 2-(tetrazol-5-yl)ethyl, 3-(tetrazol-5-yl)propyl or4-(tetrazol4-yl)butyl.

Thiazolinyl-lower alkoxy is, e.g., thiazolinyl-C₁-C₄alkoxy, such asthiazolinylmethoxy, 2-thiazolinylmethoxy or 3thiazolinylpropyloxy.

Thiazolinyl-lower alkyl is, e.g., thiazolinyl-C₁-C₄alkyl, such asthiazolinylmethyl, 2-thiazolinylethyl or 3-thiazolinylpropyl.

Thiazolyl-lower alkoxy is, e.g., thiazolyl-C₁-C₄alkoxy, such asthiazolylmethoxy, 2-thiazolylethoxy or 3-thiazolylpropyloxy.

Thiazolyl-lower alkyl is, e.g., thiazolyl-C₁-C₄alkyl, such asthiazolylmethyl, 2-thiazolylethyl or 3-thiazolyipropyl.

Thiomorpholino-lower alkyl or S,S-dioxothiomorpholino-lower alkyl is,e.g., thiomorpholino-C₁-C₄alkyl, such as -methyl or -ethyl, orS,S-dioxothiomorpholino-C₁-C₄alkyl, such as -methyl or -ethyl.

Depending on whether asymmetric carbon atoms are present, the compoundsof the invention can be present as mixtures of isomers, especially asracemates, or in the form of pure isomers, especially optical antipodes.

Salts of compounds having salt-forming groups are especially acidaddition salts, salts with bases or, where several salt-forming groupsare present, can also be mixed salts or internal salts.

Salts are especially the pharmaceutically acceptable or non-toxic saltsof compounds of formula (1).

Such salts are formed, e.g., by compounds of formula (I) having an acidgroup, e.g., a carboxy group or a sulfo group, and are, e.g., saltsthereof with suitable bases, such as non-toxic metal salts derived frommetals of groups Ia, Ib, IIa and IIb of the Periodic Table of theElements, e.g., alkali metal salts, especially lithium, sodium orpotassium salts; or alkaline earth metal salts, e.g., magnesium orcalcium salts; also zinc salts or ammonium salts, as well as saltsformed with organic amines, such as unsubstituted or hydroxy-substitutedmono-, di- or tri-alkylamines, especially mono-, di- or tri-loweralkylamines; or with quaternary ammonium bases, e.g., with methyl-,ethyl-, diethyl- or triethyl-amine; mono-, his- or tris-(2-hydroxy-loweralkyl)-amines, such as ethanol-, diethanol- or triethanol-amine;tris-(hydroxymethyl)-methylamine or 2-hydroxy-tert-butylamines;N,N-di-lower alkyl-N-(hydroxy-lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)-amine or N-methyl-D-glucamine; orquaternary ammonium hydroxides, such as tetrabutylammonium hydroxide.The compounds of formula (I) having a basic group, e.g., an amino group,can form acid addition salts, e.g., with suitable inorganic acids, e.g.,hydrohalic acids, such as hydrochloric acid or hydrobromic acid; orsulfuric acid with replacement of one or both protons; phosphoric acidwith replacement of one or more protons, e.g., orthophosphoric acid ormetaphosphoric acid; or pyrophosphoric acid with replacement of one ormore protons; or with organic carboxylic, sulfonic, sulfo or phosphonicacids; or N-substituted sulfamic acids, e.g., acetic acid, propionicacid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid,methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconicacid, glucaric acid, glucuronic acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinicacid or isonicotinic acid, as well as with amino acids, such as theα-amino acids mentioned hereinbefore; and with methanesulfonic acid,ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonicacid, benzenesulfonic acid, 4-toluenesulfonic acid,naphthalene-2-sulfonic acid, 2- or 3-phosphoglycerate,glucose-6-phosphate or N-cyclohexylsulfamic acid (forming cyclamates);or with other acidic organic compounds, such as ascorbic acid. Compoundsof formula (I) having acid and basic groups can also form internalsalts.

For isolation and purification purposes it is also possible to usepharmaceutically unacceptable salts.

The compounds of the present invention have enzyme-inhibitingproperties. In particular, they inhibit the action of the natural enzymerenin. The latter passes from the kidneys into the blood where iteffects the cleavage of angiotensinogen, releasing the decapeptideangiotensin I which is then cleaved in the lungs, the kidneys and otherorgans to form the octapeptide angiotensinogen II. The octapeptideincreases blood pressure both directly by arterial vasoconstriction andindirectly by liberating from the adrenal glands thesodium-ion-retaining hormone aldosterone, accompanied by an increase inextracellular fluid volume. That increase can be attributed to theaction of angiotensin II. Inhibitors of the enzymatic activity of reninbring about a reduction in the formation of angiotensin I. As a result asmaller amount of angiotensin II is produced. The reduced concentrationof that active peptide hormone is the direct cause of the hypotensiveeffect of renin inhibitors.

Thus, the compounds of the present invention may be employed for thetreatment of hypertension, atherosclerosis, unstable coronary syndrome,congestive heart failure, cardiac hypertrophy, cardiac fibrosis,cardiomyopathy postinfarction, unstable coronary syndrome, diastolicdysfunction, chronic kidney disease, hepatic fibrosis, complicationsresulting from diabetes, such as nephropathy, vasculopathy andneuropathy, diseases of the coronary vessels, restenosis followingangioplasty, raised intra-ocular pressure, glaucoma, abnormal vasculargrowth, hyperaldosteronism, cognitive impairment, alzheimers, dementia,anxiety states and cognitive disorders.

The groups of compounds mentioned below are not to be regarded asexclusive; rather, e.g., in order to replace general definitions withmore specific definitions, parts of those groups of compounds can beinterchanged or exchanged for the definitions given above, or omitted,as appropriate.

Preferred are the compounds of formula (1), designated as the A group,wherein

-   -   R⁹ is lower alkyl, optionally substituted cycloalkyl (alkyl, OH,        alkoxy, alkoxy-alkyl, halogens), optionally substituted        cycloalkyl-alkyl (OH, alkoxy, alkoxy-alkyl, halogens on        cycloalkyl), cycloalkyl carboxamides, N-mono or N,N-dialkyl        substituted cycloalkyl carboxamides, optionally substituted        aryl-alkyl, free or aliphatically esterified or etherified        hydroxy-lower alkyl; amino-lower alkyl that is unsubstituted or        N-lower alkanoylated or N-mono- or N,N-di-lower alkylated or        N,N-di-substituted by lower alkylene, by hydroxy-, lower alkoxy-        or lower alkanoyloxy-lower alkylene, by unsubstituted or        N′-lower alkanoylated or N′-lower alkylated aza-lower alkylene,        by oxa-lower alkylene or by optionally S-oxidised thia-lower        alkylene, free or esterified or amidated carboxy-lower alkyl,        free or esterified or amidated dicarboxy-lower alkyl, free or        esterified or amidated carboxy-(hydroxy)-lower alkyl, free or        esterified or amidated carboxycycloalkyl-lower alkyl,        cyano-lower alkyl, lower alkanesulfonyl-lower alkyl,        unsubstituted or N-mono- or N,N-di-lower alkylated        thiocarbamoyl-lower alkyl, unsubstituted or N-mono- or        N,N-di-lower alkylated sulfamoyl-lower alkyl, or a heteroaryl        radical bonded via a carbon atom and optionally hydrogenated        and/or oxo-substituted, or lower alkyl substituted by a        heteroaryl radical bonded via a carbon atom and optionally        hydrogenated and/or oxo-substituted;        or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the A group wherein

-   -   R¹ and R⁴ are hydrogen;    -   R² is lower alkoxy-lower alkoxy;    -   R³ is halogen or mono, di or tri-halo-substituted alkyl;        or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the A group wherein thehalogen/halo is fluorine or chlorine;

or a pharmaceutically acceptable salt thereof.

More preferred are the compounds in the A group wherein

-   -   R³ is fluorine or trifluoromethyl;        or a pharmaceutically acceptable salt thereof.

Most preferred are the compounds in the A group wherein R² is in themeta position and R³ is in the para position;

or a pharmaceutically acceptable salt thereof.

Most preferred are also the compounds in the A group wherein R³ is inthe ortho position;

or a pharmaceutically acceptable salt thereof.

Most preferred are also the compounds in the A group wherein R³ is inthe meta position;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the A group, designated as the Bgroup, wherein R² is in the meta position and is lower alkoxy-loweralkoxy optionally substituted by halogen(s);

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the B group wherein thehalogen(s) is fluorine or chlorine;

or a pharmaceutically acceptable salt thereof.

More preferred are the compounds in the B group wherein the halogen(s)is fluorine;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the B group, designated as the Cgroup, wherein R³ is lower alkoxy substituted by halogen(s);

or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the C group wherein the halogen(s) isfluorine or chlorine;

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the C group wherein thehalogen(s) is fluorine;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the B group, designated as the Dgroup, wherein R³ is in the para position;

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the D group wherein R³ ismethoxy;

or a pharmaceutically acceptable salt thereof.

Further preferred are also the compounds in the D group wherein R³ istrifluoro-methoxy;

or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds of formula (I) wherein

-   -   R³ is located at the para position and is halogen;        or a pharmaceutically acceptable salt thereof.

Preferred are also the δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amidecompounds of formula (I), designated as the E group, having formula (Ia)

wherein

-   -   R¹ is hydrogen, halogen, optionally halogenated alkyl,        cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy,        lower alkoxy-lower alkoxy or free or esterified or amidated        carboxy-lower alkoxy or lower alkyl;    -   R² is hydrogen, halogen, optionally halogenated lower alkyl,        hydroxy, cycloalkyl, cycloalkoxy, optionally halogenated lower        alkoxy-lower alkyl, optionally substituted lower alkoxy-lower        alkoxy, cycloalkoxy-lower alkyl; optionally lower alkanoylated,        halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower        alkyl that is unsubstituted or substituted by lower alkyl, by        lower alkanoyl and/or by lower alkoxy-carbonyl; optionally        hydrogenated heteroaryl-lower alkyl; amino-lower alkoxy that is        substituted by lower alkyl, by lower alkanoyl and/or by lower        alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, cycloalkoxy,        lower alkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower        alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-lower        alkenyl-oxy, lower alkenyloxy-lower alkyl, lower alkanoyl-lower        alkoxy, optionally S-oxidised lower alkylthio-lower alkoxy,        lower alkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy,        aryl-lower alkyl, aryl-lower alkoxy, optionally hydrogenated        heteroaryl-lower alkoxy, optionally hydrogenated        heteroaryl-lower alkyl, cyano-lower alkoxy, cyano-lower alkyl,        free or esterified or amidated carboxy-lower alkoxy or free or        esterified or amidated carboxy-lower alkyl;    -   R³ and R⁴ are independently hydrogen, halogen, optionally        halogenated lower alkyl, hydroxy, optionally halogenated lower        alkoxy or cycloalkoxy, lower alkoxy-lower alkyl,        cycloalkoxy-lower alkyl, hydroxy-lower alkyl, optionally        S-oxidised lower alkylthio-lower alkyl, optionally hydrogenated        heteroarylthio-lower alkyl, optionally hydrogenated        heteroaryl-lower alkyl; amino-lower alkyl that is unsubstituted        or N-mono- or N,N-di-lower alkylated, N-lower alkanoylated or        N-lower alkanesulfonylated or N,N-disubstituted by lower        alkylene, by unsubstituted or N′-lower alkylated or N′-lower        alkanoylated aza-lower alkylene, by oxa-lower alkylene or by        optionally S-oxidised thia-lower alkylene; cyano-lower alkyl,        free or esterified or amidated carboxy-lower alkyl, cycloalkyl,        aryl, hydroxy, lower alkoxy, cycloalkoxy, lower alkoxy-lower        alkoxy, cycloalkoxy-lower alkoxy, hydroxy-lower alkoxy,        aryl-lower alkoxy, optionally halogenated lower alkoxy,        optionally S-oxidised lower alkylthio-lower alkoxy, optionally        hydrogenated heteroaryl-lower alkoxy, optionally hydrogenated        hetero-arylthio-lower alkoxy; amino-lower alkoxy that is        unsubstituted or N-mono- or N,N-di-lower alkylated, N-lower        alkanoylated or N-lower alkanesulfonylated or substituted by        lower alkylene, by unsubstituted or N′-lower alkylated or        N′-lower alkanoylated aza-lower alkylene, by oxalower alkylene        or by optionally S-oxidised thia-lower alkylene; cyano-lower        alkoxy or free or esterified or amidated carboxy-lower alkoxy;        or    -   R⁴ together with R³ is lower alkeneoxy, alkylenedioxy or a        fused-on aryl, optionally hydrogenated heteroaryl or cycloalkyl        ring;    -   X is methylene, hydroxymethylene, oxygen, optionally lower alkyl        substituted nitrogen or optionally oxidized sulfur;    -   R⁵ is lower alkyl or cycloalkyl;    -   R⁵ is hydrogen, lower alkyl, hydroxy, alkoxy or halogen;    -   R⁷ is unsubstituted or N-mono- or N,N-di-lower alkylated or        N-lower alkanoylated amino;    -   R⁸ is lower alkyl, lower alkenyl, cycloalkyl or aryl-lower        alkyl;    -   R⁹ is optionally substituted lower alkyl, optionally substituted        cycloalkyl, optionally substituted cycloalkyl-alkyl, cycloalkyl        carboxamides, N-mono or N,N-dialkyl substituted cycloalkyl        carboxamides, optionally substituted aryl-alkyl, optionally        substituted aryloxy-aryl, optionally substituted        heteroaryloxy-alkyl, free or aliphatically esterified or        etherified hydroxy-lower alkyl; amino-lower alkyl that is        unsubstituted or N-lower alkanoylated or N-mono- or N,N-di-lower        alkylated or N,N-di-substituted by lower alkylene, by hydroxy-,        lower alkoxy- or lower alkanoyloxy-lower alkylene, by        unsubstituted or N′-lower alkanoylated or N′-lower alkylated        aza-lower alkylene, by oxa-lower alkylene or by optionally        S-oxidised thia-lower alkylene, free or esterified or amidated        carboxy-lower alkyl, free or esterified or amidated        dicarboxy-lower alkyl, free or esterified or amidated        carboxy-(hydroxy)-lower alkyl, free or esterified or amidated        carboxycycloalkyl-lower alkyl, cyano-lower alkyl, lower        alkanesulfonyl-lower alkyl, unsubstituted or N-mono- or        N,N-di-lower alkylated thiocarbamoyl-lower alkyl, unsubstituted        or N-mono- or N,N-di-lower alkylated sulfamoyl-lower alkyl, or a        heteroaryl radical bonded via a carbon atom and optionally        hydrogenated and/or oxo-substituted, or lower alkyl substituted        by a heteroaryl radical bonded via a carbon atom and optionally        hydrogenated and/or oxo-substituted;        or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the E group wherein

-   -   R⁹ is cycloalkyl substituted with alkyl, hydroxy, alkoxy,        alkoxy-alkoxy or halogens; cycloalkyl-alkyl optionally        substituted with alkyl, hydroxy, alkoxy, alkoxy-alkoxy or        halogens on cycloalkyl or halogens on alkyl or halongens on        alkoxy; cycloalkyl carboxamides; N-mono or N,N-dialkyl        substituted cycloalkyl carboxamides; or optionally substituted        aryl-alkyl;        or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the E group, designated as the Fgroup, wherein

-   -   R⁹ is hydrogen; halogenated alkyl; optionally substituted        aryl-alkyl, optionally substituted aryloxy-alkyl, cycloalkyl        substituted by 1 to 3 substituents selected from the group        consisting of alkenyl, alkynyl, halo, hydroxy, alkoxy,        alkoxy-alkoxy, alkylthio, arylthio, aryl-alkoxy, carbamoyl,        sulfamoyl, sulfonyl, optionally substituted amino, cyano,        carboxy, alkoxycarbonyl, aryl, aryloxy, heterocyclyl or alkyl        optionally substituted by amino, halo, hydroxy, alkoxy, carboxy,        alkoxycarbonyl, carbamoyl or heterocyclyl; or optionally        substituted cycloalkyl-alkyl;        or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the F group wherein

-   -   R¹ is hydrogen;    -   R² is C₁-C₄ alkoxy-C₁-C₄ alkoxy or C₁-C₄ alkoxy-C₁-C₄ alkyl;    -   R³ is C₁-C₄ alkyl or C₁-C₄ alkoxy;    -   R⁴ is hydrogen;    -   X is methylene;    -   R⁵ is lower alkyl;    -   R⁶ is hydrogen;    -   R⁷ is unsubstituted amino;    -   R⁸ is branched C₃-C₄ alkyl;    -   R⁹ is optionally substituted cycloalkyl-alkyl;        or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the F group wherein

-   -   R² is 3-methoxypropyloxy;    -   R³ is methoxy;    -   R⁵ is isopropyl;    -   R⁸ is isopropyl;        or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the F group, designated as the Ggroup, wherein

-   -   R¹ is hydrogen;    -   R² is C₁-C₄ alkoxy-C₁-C₄ alkoxy or C₁-C₄ alkoxy-C₁-C₄ alkyl;    -   R³ is C₁-C₄ alkyl or C₁-C₄ alkoxy;    -   R⁴ is hydrogen;    -   X is methylene;    -   R⁵ is lower alkyl;    -   R⁶ is hydrogen;    -   R⁷ is unsubstituted amino;    -   R⁸ is branched C₁-C₄ alkyl;    -   R⁹ is optionally substituted aryl-alkyl; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the G group wherein

-   -   R² is 3-methoxypropyloxy;    -   R³ is methoxy;    -   R⁵ is isopropyl;    -   R⁸ is isopropyl;        or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the G group wherein aryl-alkyl isalkyl substituted with phenyl;

or a pharmaceutically acceptable salt thereof.

Further preferred are the compounds in the G group wherein aryl-alkyl ismethyl substituted with phenyl.

More preferred are the compounds in the G group wherein

-   -   R² is 3-methoxypropyloxy;    -   R³ is methoxy;    -   R⁵ is isopropyl;    -   R⁸ is isopropyl;        or a pharmaceutically acceptable salt thereof.

As a result of the close relationship between the novel compounds infree form and in the form of their salts, hereinabove and hereinbelowany reference to the free compounds and their salts is to be understoodas including also the corresponding salts and free compounds,respectively, as appropriate and expedient.

The compounds of the present invention may generally be prepared bythose methods disclosed in U.S. Pat. No. 5,559,111, incorporated hereinby reference in its entirety as if set forth in full herein.

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of a pharmacologicallyactive compound of the instant invention, alone or in combination withone or more pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the present invention arethose suitable for enteral, such as oral or rectal, transdermal andparenteral administration to mammals, including man, to inhibit reninactivity, and for the treatment of conditions associated with reninactivity. Such conditions include hypertension, atherosclerosis,unstable coronary syndrome, congestive heart failure, cardiachypertrophy, cardiac fibrosis, cardiomyopathy postinfarction, unstablecoronary syndrome, diastolic dysfunction, chronic kidney disease,hepatic fibrosis, complications resulting from diabetes, such asnephropathy, vasculopathy and neuropathy, diseases of the coronaryvessels, restenosis following angioplasty, raised intra-ocular pressure,glaucoma, abnormal vascular growth, hyperaldosteronism, cognitiveimpairment, alzheimers, dementia, anxiety states and cognitivedisorders.

Thus, the pharmacologically active compounds of the invention may beemployed in the manufacture of pharmaceutical compositions comprising aneffective amount thereof in conjunction or admixture with excipients orcarriers suitable for either enteral or parenteral application.Preferred are tablets and gelatin capsules comprising the activeingredient together with:

-   a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,    cellulose and/or glycine;-   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or    calcium salt and/or polyethyleneglycol; for tablets also-   c) binders, e.g., magnesium aluminum silicate, starch paste,    gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose    and or polyvinylpyrrolidone; if desired-   d) disintegrants, e.g., starches, agar, alginic acid or its sodium    salt, or effervescent mixtures; and/or-   e) absorbants, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions.

Said compositions may be sterilized and/or contain adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers. Inaddition, they may also contain other therapeutically valuablesubstances. Said compositions are prepared according to conventionalmixing, granulating or coating methods, respectively, and contain about0.1-75%, preferably about 1-50%, of the active ingredient.

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpre-determined rate over a prolonged period of time, and means to securethe device to the skin.

Accordingly, the present invention provides pharmaceutical compositionsas described above for the treatment of conditions mediated by reninactivity, preferably, hypertension, atherosclerosis, unstable coronarysyndrome, congestive heart failure, cardiac hypertrophy, cardiacfibrosis, cardiomyopathy postinfarction, unstable coronary syndrome,diastolic dysfunction, chronic kidney disease, hepatic fibrosis,complications resulting from diabetes, such as nephropathy, vasculopathyand neuropathy, diseases of the coronary vessels, restenosis followingangioplasty, raised intra-ocular pressure, glaucoma, abnormal vasculargrowth, hyperaldosteronism, cognitive impairment, alzheimers, dementia,anxiety states and cognitive disorders.

The pharmaceutical compositions may contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include:

-   a) antidiabetic agents such as insulin, insulin derivatives and    mimetics; insulin secretagogues such as the sulfonylureas, e.g.,    Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea    receptor ligands such as meglitinides, e.g., nateglinide and    repaglinide; peroxisome proliferator-activated receptor (PPAR)    ligands; protein tyrosine phosphatase-1B (PTP-1B) inhibitors such as    PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as    SB-517955, SB-4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR    ligands such as GW-0791 and AGN-194204; sodium-dependent glucose    cotransporter inhibitors such as T-1095; glycogen phosphorylase A    inhibitors such as BAY R3401; biguanides such as metformin;    alpha-glucosidase inhibitors such as acarbose; GLP-1 (glucagon like    peptide-1), GLP-1 analogs such as Exendin-4 and GLP-1 mimetics; and    DPPIV (dipeptidyl peptidase IV) inhibitors such as LAF237;-   b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme    A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin,    simvastatin, pravastatin, cerivastatin, mevastatin, velostatin,    fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin;    squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR    (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid    and aspirin;-   c) anti-obesity agents such as orlistat; and-   d) anti-hypertensive agents, e.g., loop diuretics such as ethacrynic    acid, furosemide and torsemide; angiotensin converting enzyme (ACE)    inhibitors such as benazepril, captopril, enalapril, fosinopril,    lisinopril, moexipril, perinodopril, quinapril, ramipril and    trandolapril; inhibitors of the Na-K-ATPase membrane pump such as    digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors    such as omapatrilat, sampatrilat and fasidotril; angiotensin II    antagonists such as candesartan, eprosartan, irbesartan, losartan,    telmisartan and valsartan, in particular valsartan; β-adrenergic    receptor blockers such as acebutolol, atenolol, betaxolol,    bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol;    inotropic agents such as digoxin, dobutamine and milrinone; calcium    channel blockers such as amlodipine, bepridil, diltiazem,    felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and    verapamil; aldosterone receptor antagonists; and aldosterone    synthase inhibitors.

Other specific anti-diabetic compounds are described by Patel Mona inExpert Opin Investig Drugs, 2003, 12(4), 623-633, in the FIGS. 1to 7,which are herein incorporated by reference. A compound of the presentinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The structure of the therapeutic agents identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g., PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

Accordingly, the present invention provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of theinvention in combination with a therapeutically effective amount ofanother therapeutic agent, preferably selected from anti-diabetics,hypolipidemic agents, anti-obesity agents or anti-hypertensive agents,most preferably from antidiabetics, anti-hypertensive agents orhypolipidemic agents as described above.

The present invention further relates to pharmaceutical compositions asdescribed above for use as a medicament.

The present invention further relates to use of pharmaceuticalcompositions or combinations as described above for the preparation of amedicament for the treatment of conditions mediated by renin activity,preferably, hypertension, atherosclerosis, unstable coronary syndrome,congestive heart failure, cardiac hypertrophy, cardiac fibrosis,cardiomyopathy postinfarction, unstable coronary syndrome, diastolicdysfunction, chronic kidney disease, hepatic fibrosis, complicationsresulting from diabetes, such as nephropathy, vasculopathy andneuropathy, diseases of the coronary vessels, restenosis followingangioplasty, raised intra-ocular pressure, glaucoma, abnormal vasculargrowth, hyperaldosteronism, cognitive impairment, alzheimers, dementia,anxiety states and cognitive disorders.

Thus, the present invention also relates to a compound of formula (I)for use as a medicament, to the use of a compound of formula (I) for thepreparation of a pharmaceutical composition for the prevention and/ortreatment of conditions mediated by renin activity, and to apharmaceutical composition for use in conditions mediated by reninactivity comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable diluent or carrier therefor.

The present invention further provides a method for the preventionand/or treatment of conditions mediated by renin activity, whichcomprises administering a therapeutically effective amount of a compoundof the present invention.

A unit dosage for a mammal of about 50-70 kg may contain between about 1mg and 1000 mg, advantageously between about 5-600 mg of the activeingredient. The therapeutically effective dosage of active compound isdependent on the species of warm-blooded animal (mammal), the bodyweight, age and individual condition, on the form of administration, andon the compound involved.

In accordance with the foregoing the present invention also provides atherapeutic combination, e.g., a kit, kit of parts, e.g., for use in anymethod as defined herein, comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, to be used concomitantly or insequence with at least one pharmaceutical composition comprising atleast another therapeutic agent, preferably selected from anti-diabeticagents, hypolipidemic agents, anti-obesity agents or anti-hypertensiveagents. The kit may comprise instructions for its administration.

Similarly, the present invention provides a kit of parts comprising: (i)a pharmaceutical composition of the invention; and (ii) a pharmaceuticalcomposition comprising a compound selected from an anti-diabetic, ahypolipidemic agent, an anti-obesity agent, an anti-hypertensive agent,or a pharmaceutically acceptable salt thereof, in the form of twoseparate units of the components (i) to (ii).

Likewise, the present invention provides a method as defined abovecomprising co-administration, e.g., concomitantly or in sequence, of atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, and a second drug substance,said second drug substance being an anti-diabetic, a hypolipidemicagent, an anti-obesity agent or an anti-hypertensive agent, e.g., asindicated above.

Preferably, a compound of the invention is administered to a mammal inneed thereof.

Preferably, a compound of the invention is used for the treatment of adisease which responds to modulation of renin activity.

Preferably, the condition associated with renin activity is selectedfrom hypertension, atherosclerosis, unstable coronary syndrome,congestive heart failure, cardiac hypertrophy, cardiac fibrosis,cardiomyopathy postinfarction, unstable coronary syndrome, diastolicdysfunction, chronic kidney disease, hepatic fibrosis, complicationsresulting from diabetes, such as nephropathy, vasculopathy andneuropathy, diseases of the coronary vessels, restenosis followingangioplasty, raised intra-ocular pressure, glaucoma, abnormal vasculargrowth, hyperaldosteronism, cognitive impairment, alzheimers, dementia,anxiety states and cognitive disorders.

Finally, the present invention provides a method or use which comprisesadministering a compound of formula (I) in combination with atherapeutically effective amount of an anti-diabetic agent, ahypolipidemic agent, an anti-obesity agent or an anti-hypertensiveagent.

Ultimately, the present invention provides a method or use whichcomprises administering a compound of formula (I) in the form of apharmaceutical composition as described herein.

As used throughout the specification and in the claims, the term“treatment” embraces all the different forms or modes of treatment asknown to those of the pertinent art and in particular includespreventive, curative, delay of onset and/or progression, and palliativetreatment.

The above-cited properties are demonstrable in vitro and in vivo testsusing advantageously mammals, e.g., mice, rats, rabbits, dogs, monkeysor isolated organs, tissues and preparations thereof. Said compounds canbe applied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo either enterally, parenterally, advantageouslyintravenously, e.g., as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻³ molar and 10⁻¹⁰ molarconcentrations. A therapeutically effective amount in vivo may rangedepending on the route of administration, between about 0.001 and 500mg/kg, preferably between about 0.1 and 100 mg/kg.

As described above, the compounds of the present invention haveenzyme-inhibiting properties. In particular, they inhibit the action ofthe natural enzyme renin. Renin passes from the kidneys into the bloodwhere it effects the cleavage of angiotensinogen, releasing thedecapeptide angiotensin I which is then cleaved in the lungs, thekidneys and other organs to form the octapeptide angiotensin II. Theoctapeptide increases blood pressure both directly by arterialvasoconstriction and indirectly by liberating from the adrenal glandsthe sodium-ion-retaining hormone aldosterone, accompanied by an increasein extracellular fluid volume which increase can be attributed to theaction of angiotensin II. Inhibitors of the enzymatic activity of reninlead to a reduction in the formation of angiotensin I, and consequentlya smaller amount of angiotensin II is produced. The reducedconcentration of that active peptide hormone is the direct cause of thehypotensive effect of renin inhibitors.

The action of renin inhibitors may be demonstrated inter aliaexperimentally by means of in vitro tests, the reduction in theformation of angiotensin I being measured in various systems (humanplasma, purified human renin together with synthetic or natural reninsubstrate).

Inter alia the following in vitro tests may be used:

An extract of human renin from the kidney (0.5 mGU [milli-Goldblattunits]/mL) is incubated for one h at 37° C. and pH 7.2 in 1 M aqueous2-N-(tris-hydroxymethylmethyl)-amino-ethanesulfonic acid buffer solutionwith 23 μg/mL of synthetic renin substrate, the tetradecapeptideH-Asp-Arg-Val-Tyr-Ile-His-ProPhe-His-Leu-Leu-Val-Tyr-Ser-OH. The amountof angiotensin I formed is determined by radioimmunoassay. Each of theinhibitors according to the invention is added to the incubation mixtureat different concentrations. The IC₅₀ is defined as the concentration ofa particular inhibitor that reduces the formation of angiotensin I by50%.

Recombinant human renin (expressed in Chinese Hamster Ovary cells andpurified using standard methods) at 4 nM concentration is incubated withtest compound at various concentrations for 1 h at RT in 0.1 M Tris-HClbuffer, pH 7.4, containing 0.05 M NaCl, 0.5 mM EDTA and 0.05% CHAPS.Synthetic peptide substrateArg-Glu(EDANS)lle-His-Pro-Phe-His-Leu-Val-IIe_His_Thr-Lys(DABCYL)-Arg9is added to a final concentration of 2 μM and increase in fluorescenceis recorded at an excitation wave-length of 340 nm and at an emissionwave-length of 485 nm in a microplate spectro-fluorimeter. IC₅₀ valuesare calculated from percentage of inhibition of renin activity as afunction of test compound concentration (Fluorescence Resonance EnergyTransfer, FRET, assay).

Recombinant human renin (expressed in Chinese Hamster Ovary cells andpurified using standard methods) at 1 nM concentration is incubated withtest compound at various concentrations for 1.5 h at 37° C. in 0.1 MTris/HCl pH 7.4 containing 0.05 M NaCl, 0.5 mM EDTA and 0.025% (w/v)CHAPS. Synthetic peptide substrateAc-IIe-His-Pro-Phe-His-Leu-Val-IIe-His-Asn-Lys-[DY-505-X5] is added to afinal concentration of 5 μM. The enzyme reaction is stopped by adding 6μL of 1.0% TFA The product of the reaction is separated by HPLC andquantified by spectrophotometric measurement at 505 nM wave-length. IC₅₀values are calculated from percentage of inhibition of renin activity asa function of test compound concentration.

Recombinant human renin (expressed in Chinese Hamster Ovary cells andpurified using standard methods) at 3.3 nM concentration,1251-NVP-AJ1891-NX-1 (0.27 μCi/mL) and streptavidin-SPA (0.67 mg/mL)beads are incubated with test compound at various concentrations for 2.0h at RT in 0.1 M Tris/HCl pH 7.4 containing 0.5M NaCl and 0.5% (wN)Brij35. At the end of the incubation time, the plates are centrifuged(55g, 60 seconds) and counted in a Wallac MicroBeta reader. IC₅₀ valuesare calculated from percentage of displacement of radioligand binding torenin as a function of test compound concentration.

In animals deficient in salt, renin inhibitors bring about a reductionin blood pressure. Human renin may differ from the renin of otherspecies. In order to test inhibitors of human renin, primates,e.g.,marmosets (Callithrix jacchus) may be used, because human renin andprimate renin are substantially homologous in the enzymatically activeregion. Inter alia the following in vivo tests may be used:

The test compounds are tested on normotensive marmosets of both sexeshaving a body weight of approximately 350 g that are conscious, allowedto move freely and in their normal cages. The blood pressure and heartrate are measured via a catheter in the descending aorta and recordedradiometrically. The endogenous release of renin is stimulated by thecombination of a 1-week low-salt diet and a single intramuscularinjection of furosemide(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (5mg/kg). 16 h after the injection of furosemide the test compounds areadministered either directly into the femoral artery using an injectioncannula or, in the form of a suspension or solution, via an oesophagealtube into the stomach, and their action on the blood pressure and heartrate are evaluated. In the in vivo test described, the compounds of thepresent invention have hypotensive action at doses of from approximately0.003 to approximately 1 mg/kg i.v. and at doses of from approximately0.3 to approximately 100 mg/kg p.o.

Alternatively, renin inhibitors may be tested on male normotensivemarmosets weighing 250 to 500 g that are conscious, allowed to movefreely and in their normal cages. The blood pressure, and heart rate aremeasured via a catheter placed in the descending aorta and recordedradiometrically. Electrocardiogram are obtained by placing electrodes oftransmitter in lead II. The endogenous release of renin is stimulated bytwo intramuscular injection of furosemide(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid) (10mg/kg) 43 and 19 hours prior compound application. Test compounds areadministered either directly into the femoral artery using an injectioncannula or, in the form of a suspension or solution, via an oesophagealtube into the stomach, and their action on the blood pressure, heartrate and ECG are evaluated. In the in vivo test described, compounds ofthe present invention have hypotensive action at doses of fromapproximately 0.003 to approximately 0.3 mg/kg i.v. and at doses of fromapproximately 0.31 to approximately 30 mg/kg p.o.

The compounds of the present invention also have the property ofregulating, especially reducing, intra-ocular pressure.

The extent of the reduction in intra-ocular pressure afteradministration of a pharmaceutical active ingredient of formula (I)according to the present invention can be determined, for example, inanimals, for example rabbits or monkeys. Two typical experimentalprocedures that illustrate the present invention, but are not limited toin any way, are described hereinafter.

The in vivo test on a rabbit of the “Fauve de Bourgogne” type todetermine the intra-ocular-pressure-reducing activity of topicallyapplied compositions can be designed, for example, as follows: Theintra-ocular pressure (IOP) is measured using an aplanation tonometerboth before the experiment and at regular intervals of time. After alocal anaesthetic has been administered, the suitably formulated testcompound is applied topically in a precisely defined concentration (e.g.0.000001-5% by weight) to one eye of the animal in question. Thecontralateral eye is treated, for example, with physiological saline.The measured values thus obtained are evaluated statistically.

The in vivo tests on monkeys of the species Macaca Fascicularis todetermine the intra-ocular-pressure-reducing activity of topicallyapplied compositions can be carried out, e.g., as follows: The suitablyformulated test compound is applied in a precisely defined concentration(e.g. 0.000001-5% by weight) to one eye of each monkey. The other eye ofthe monkey is treated correspondingly, for example with physiologicalsaline. Before the start of the test the animals are anaesthetised withintramuscular injections of, for example, ketamine. At regular intervalsof time, the intra-ocular pressure (IOP) is measured. The test iscarried out and evaluated in accordance with the rules of “goodlaboratory practice” (GLP).

Illustrative of the invention, the compound of Example 29 demonstratesinhibition of renin activity with an IC₅₀ value of about 0.3 nM in theFRET assay.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, all evaporations are performed under reduced pressure,preferably between about 10 and 100 mmHg (=20-133 mbar). The structureof final products, intermediates and starting materials is confirmed bystandard analytical methods, e.g., microanalysis, melting point (m.p.)and spectroscopic characteristics, e.g., MS, LC/MS, IR, NMR. In general,abbreviations used are those conventional in the art.

EXAMPLE 1 General Procedure (I)

a)(2S,4S,5S,7S)-5-tert-Butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid

Triethylamine (NEt₃) (7.2 mL, 51.6 mmol, 3.0 equiv.) followed bydimethylamino-pyridine (DMAP) (640 mg, 5.2 mmol, 0.3 equiv.) is added toa solution of(2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (9.53 g, 17.2 mmol, 1.0 equiv.) and TBDMSCI (10.3 g, 68.7 mmol, 4.0equiv.) in dimethylformamide (DMF) (100 mL) at room temperature (RT).The reaction mixture is stirred at RT for 16 hours before water (H₂O) isadded. Extraction with ethyl acetate (EtOAc), drying [sodium sulphate(Na₂SO₄)] and evaporation of the solvent affords the crude product.Flash column chromatography [600 g silicon dioxide (SiO₂), hexane:EtOAc5:1] yields the double TBDMS-protected product as a colorless oil.

A portion thereof (904 mg, 1.24 mmol, 1.0 equiv.) is dissolved in methylalcohol (MeOH) (20 mL) and 1 M HCl (2 mL, 2 mmol, 1.6 equiv.) is added.The mixture is stirred at RT for 10 minutes before 1 M sodium hydroxide(NaOH) (2 mL) followed by H₂O and a 10% citric acid solution are addedfor workup. Extraction with EtOAc, drying (Na₂SO₄) of the combinedorganic extracts and evaporation of the solvent give the crude productwhich is purified by flash column chromatography [50 g SiO₂, CH₂Cl₂:MeOH(9:1)] to afford the desired product as a colorless oil. MS (LC-MS):691.3 [M+Na]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5 minutes, 95%CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 7.63 minutes.

b)((1S,2S,4S)-4-Benzylcarbamoyl-2-(tert-butyl-dimethyl-silanyloxy)-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamicacid tert-butyl ester

HBTU (400 mg, 1.03 mmol, 1.2 equiv.) is added to a solution of(2S,4S,5S,7S)-5-tert-butoxycarbonylamino-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (575 mg, 0.86 mmol, 1.0 equiv.) in acetonitrile (CH₃CN) (15 mL) andDMF (1 mL) at 0° C. After 5 minutes, a solution of benzylamine (94 μL,0.86 mmol, 1.0 equiv.) and Net₃ (1.2 mL, 8.6 mmol, 10 equiv.) in CH₃CN(3 mL) is added and the reaction mixture is stirred at room temperaturefor 5 minutes. For workup EtOAc is added and the organic layer is washedwith 1 N HCl, a saturated solution of sodium bicarbonate (NaHCO₃) andbrine. Drying (Na₂SO₄) of the organic phase and evaporation of thesolvent affords the crude product which is purified by flash columnchromatography [50 g SiO₂, hexane:EtOAc (4:1)] to afford the desiredproduct as a colorless foam. MS (LC-MS): 780.4 [M+Na]⁺; R_(f)[hexane:EtOAc (1:1)]: 0.65 minutes.

c)((1S,2S,4S)-4-Benzylcarbamoyl-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamicacid tert-butyl ester

TBAF.3 H₂O (302 mg, 0.96 mmol, 1.5 equiv.) is added to a solution of((1S,2S,4S)-4-benzylcarbamoyl-2-(tert-butyl-dimethyl-silanyloxy)-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamicacid tert-butyl ester (485 mg, 0.64 mmol, 1.0 equiv.) in tetrahydrofuran(THF) (6 mL) at RT. After 1 hour, H₂O is added and the mixture isextracted with EtOAc. The combined extracts are dried (Na₂SO₄) and thesolvent is evaporated. Flash column chromatography [50 g SiO₂,hexane:EtOAc (3:1)] yields the desired product as a colorless foam. MS(LC-MS): 665.3 [M+Na]⁺; R_(f) [hexane:EtOAc (1:1)]: 0.33 minutes.

d)(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid benzylamide

At 0° C. 4 N HCl/dioxane (7 mL, 28 mmol) is added to((1S,2S,4S)-4-benzylcarbamoyl-2-hydroxy-1-{(S)-2-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-5-methyl-hexyl)-carbamicacid tert-butyl ester (214 mg, 0.34 mmol, 1.0 equiv.). The resultingsolution is stirred at RT for 15 minutes whereupon a saturated solutionof NaHCO₃ is carefully added. The mixture is extracted with EtOAc, thecombined extracts are dried (Na₂SO₄) and the solvent is evaporated.Flash column chromatography [20 g SiO₂, CH₂Cl₂:MeOH (9:1) to CH₂Cl₂:MeOH(9:1) +1% NEt₃] affords the product as a colorless oil. MS (LC-MS):544.3 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.19 minutes.

EXAMPLE 2 General Procedure (II)

a)(2S,4S,5S,7S)-5-Azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid

Lithium hydroxide (LiOH).H₂O (2.18 g, 52.0 mmol) is added to a solutionof(3S,5S)-5-{(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one(20.0 g, 43.3 mmol) in dimethoxyethane (DME) (400 mL) and H₂O (200 mL)and the resulting solution is stirred at RT for 2 hours. The solvent isco-evaporated with toluene and the resulting solid is dried under highvacuum.

This residue is dissolved in DMF (160 mL) and NEt₃ (32 mL, 227.6 mmol),TBDMSOTf (41.8 mL, 182.1 mmol) and DMAP (556 mg, 4.6 mmol) are addedsequentially. The mixture is stirred at RT for 16 hours. For workup,EtOAc is added and the mixture is quenched by addition of a saturatedsolution of NaHCO₃. The organic phase is separated and the aqueous phaseis extracted with EtOAc. Evaporation of the solvent of the combinedorganic extracts affords bis-TBDMS protected product (32.4 g) whileacidification of the basic aqueous layer with 1 N HCl followed byextraction with EtOAc and evaporation of the solvent yields thecorresponding mono-silylated free acid (8.8 g). Both isolated productsare combined and subjected to flash column chromatography [hexane:EtOAc(4:1) to hexane:EtOAc (1:1)] to give the desired mono-silylated acid asa viscous oil (complete desilylation of the silyl-protected acid duringchromatography). MS (LC-MS): 616.0 [M+Na]⁺; t_(R) (HPLC, C8 column,20-95% CH₃CN/H₂O/3.5 minute, 95% CH₃CN/1 minute, flow: 0.8 mL/min.):3.93 minutes.

b)(2S,4S,5S,7S)-5-Azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2-piperidin-1-yl-ethyl)-amide

HBTU (1.20 g, 3.0 mmol) was added to a solution of(2S,4S,5S,7S)-5-azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1.50 g, 2.5 mmol) in CH₃CN (50 mL). Then 2-aminoethylpiperidine(324 mg, 2.5 mmol) and NEt₃ (3.9 mL) were added and the resultingsolution was stirred at RT for 2.5 hours. For workup, EtOAc was addedand the organic phase was washed with 1 N HCl, saturated NaHCO₃ solutionand brine. Drying of the organic phase (Na₂SO₄) and evaporation of thesolvent affords the crude product which is purified by flash columnchromatography [CH₂Cl₂:MeOH (95:5)] to give the desired product as acolorless oil. MS (LC-MS): 705.1 [M+H]⁺; t_(R) (HPLC, C18 column,10-100% CH₃CN/H₂O/5 minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3minutes, flow: 1.5 mL/min.): 6.82 minutes.

c)(2S,4S,5S,7S)-5-Azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2-piperidin-1-yl-ethyl)-amide

TBAF.3 H₂O (1.73 g, 5.5 mmol) is added to a solution of(2S,4S,5S,7S)-5-azido-4-(tert-butyl-dimethyl-silanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl[-8-methyl-nonanoicacid (2-piperidin-1-yl-ethyl)-amide (1.54 g, 2.2 mmol) in THF (15 mL).The reaction mixture is stirred at RT for 72 hours. For workup, H₂O isadded and the mixture is extracted with CH₂Cl₂. The combined organicextracts are dried (Na₂SO₄) and the solvent is evaporated. Flash columnchromatography [CH₂Cl₂:MeOH (9:1)] yields the desired product as ayellowish oil. MS (LC-MS): 590.1 [M+H]⁺; t_(R) (HPLC, C18 column,10-100% CH₃CN/H₂O/5 minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3minutes, flow: 1.5 mL/min.): 5.24 minutes.

d)(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2-piperidin-1-yl-ethyl)-amide

Palladium on carbon (Pd/C) 10% (200 mg) is added to a solution of(2S,4S,5S,7S)-5-azido4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2-piperidin-1-yl-ethyl)-amide (780 mg, 1.32 mmol) in MeOH (40 mL)under Ar. Then the reaction suspension is stirred under a atmosphere ofhydrogen (H₂) for 8 hours. The catalyst is filtered-off over Celite andwashed with MeOH. Evaporation of the solvent gives the crude productwhich is pure according to anaylsis and used without furtherpurification. MS (LC-MS): 564.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100%CH₃CN/H₂O/5 minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes,flow: 1.5 mL/min.): 4.31 minutes.

EXAMPLE 3 General Procedure (III)

(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid cyclopropylmethyl-amide

A solution of(3S,5S)-5-{(1S,3S)-1-azido-3-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one(2.00 g, 4.3 mmol) and cyclopropanemethyl amine (1.9 mL, 21.7 mmol) inacetic acid (0.78 mL) was heated at 100° C. in a sealed tube for 30minutes. Water was added and the mixture was extracted with CH₂Cl₂.Drying (Na₂SO₄) of the combined extracts and evaporation of the solventafforded the crude product which was used without further purification.

Pd/C 10% (1.10 g, 1.0 mmol) was added to a solution of the crude product(2.58 g) in MeOH (16 mL) and the reaction mixture was stirred under a H₂atmosphere for 9 hours. The catalyst was filtered-off over Celite andthe solvent was evaporated. Purification of the crude product by flashcolumn chromatography [CH₂Cl₂ to CH₂CL₂:MeOH (8:2)] afforded the desiredproduct as a colorless foam. MS (LC-MS): 508.1 [M+H]⁺; t_(R) (HPLC, C18column, 10-100% CH₃CN/H₂O/5 minutes, 100% CH₃CN/3 minutes, 100-10%CH₃CN/H₂O/3 minutes, flow: 1.5 mL/min.): 4.91 minutes.

EXAMPLE 4 General Procedure (IV)

a) 4-Bromo-1-fluoro-2-(3-methoxy-propoxy)-benzene

Azodicarbonic acid diisopropylester is added to a solution of4-bromo-1-fluoro-2-hydroxy-benzene [see Maleczak, Jr., Shi, Holmes andSmith, J Am Chem Soc, Vol. 125, No. 26, pp. 7792-7793 (2003)] (5.52 g,28.9 mmol, 1 equiv.), triphenylphosphine (8.4 g, 31.8 mmol, 1.1 equiv.)in THF (20 mL) and 3methoxypropanol (3 mL, 31.8 mmol, 1.1 equiv.) in THFat RT and the solution is stirred for 16 hours, before the solvents areevaporated. Flash column chromatography [hexane:EtOAc (9:1) tohexane:EtOAc (4:1)] affords the product as a light yellow oil. MS(LC-MS): 264.9 [M+H]⁺; R_(f) [to hexane:EtOAc (4:1)]: 0.6 minutes.

b)(3S,5S)-5-((1S,3S)-1-Azido-3-{[4-fluoro-3-(3-methoxy-propoxy)-phenyl]-hydroxy-methyl)}-4-methyl-pentyl)-3-isopropyl-dihydro-furan-2-one

To a solution of 4-bromo-1-fluoro-2-(3-methoxy-propoxy)-benzene (1.94 g,13.3 mmol, 1.4 equiv.) and N-methylmorpholine (1.6 mL, 14.7 mmol, 3equiv.) in THF (20 mL) n-butyl lithium in hexane (1.6 M, 5.5 mL, 8.8mmol, 1.8 equiv.) is added dropwise at −78° C. The solution is stirredat −78° C. for 1 hour, when a solution of MgBr₂ (14.7 mmol) in THF (50mL), freshly prepared from magnesium (0.36 g, 14.7 mmol, 3 equiv.) and1,2-dibromoethane (1.3 mL, 14.7 mmol, 3 equiv.), is added dropwise at−78° C. The reaction is stirred at the same temperature for 45 minutes,when(S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-3-methyl-butyraldehyde(1.4 g, 4.9 mmol, 1 equiv.) in THF (14 mL) is added dropwise at −78° C.The reaction mixture is stirred for an additional hour at the sametemperature, before it is quenched with satatured aqueous NH₄Cl (20 mL)and warmed to RT. The mixture is extracted with EtOAc, the combinedextracts are washed with brine, dried over Na₂SO₄ and the solvent isevaporated. Flash column chromatography [CH₂Cl₂ to CH₂Cl₂:acetone (9:1)]affords the product as a light yellow oil. MS (LC-MS): 488[M+Na]⁺; R_(f)[CH₂Cl₂:acetone (98:2)]: 0.25 minutes.

The starting material(S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxotetrahydro-furan-2-yl)-ethyl]-3-methyl-butyraldehydeis prepared according to the methods described in EP 0 678 503 B1 and EP0 678 514 A1.

c)(3S,5S)-5-{(1S,3S)-1-Amino-3-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one

A solution of isobutyric acid(S-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-1-[4-fluoro-(3methoxy-propoxy)-phenyl]-3-methyl-butylester (1.45 g, 2.7 mmol, 1 equiv.), Pd/C (10%, 2,9 g) and ethanolamine(0.17 mL, 2.7 mmol, 1 equiv.) in ethanol (135 mL) were shaken under H₂(1 atmosphere) for 24 hours. The reaction mixture is filtered, beforethe solvent is evaporated to afford the product as a light grey gum. MS(LC-MS): 424 [M+H]⁺

d)[(1S,3S)-3-[4-Fluoro-3-(3-methoxy-propoxy)-benzyl]-1-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-4-methyl-pentyl]-carbamicacid tert-butyl ester

A solution of(3S,5S)-5-{(1S,3S)-1-amino-3-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-methyl-pentyl}-3-isopropyl-dihydro-furan-2-one(1.13 g, 2.7 mmol, 1 equiv.), di-tert-butyldicarbonate (2.1 g, 9.4 mmol)and diisopropylethylamine (1.83 mL, 10.7 mmol, 4 equiv.) in CH₂Cl₂ (20mL) is stirred at RT for 164 hours. The solution is washed with aqueousHCl (1 M), saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ and thesolvents are evaporated. Flash column chromatography [CH₂Cl₂ toCH₂Cl₂:acetone (95:5)] affords the product as a light yellow oil. MS(LC-MS): 546 [M+Na]⁺; R_(f) (CH₂Cl₂:acetone (95:5)]: 0.71 minutes.

e){(1S,2S,4S)-1-{(S)-2-[4-Fluoro-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-2-hydroxy-4-1(1-hydroxymethyl-cyclopropylmethyl)-carbamoyl]-5-methyl-hexyl}-carbamicacid tert-butyl ester

[(1S,3S)-3-[4-Fluoro-3-(3-methoxy-propoxy)-benzyl]-1-((2S,4S)-isopropyl-5-oxo-tetrahydro-furan-2-yl)-4-methyl-pentyl]-carbamicacid tert-butyl ester (100 g, 0.19 mmol, 1 eq),3-amino-2,2-dimethylpropanol (0.3 g, 2.8 mmol, 15 eq) and acetic acid(0.11 μL, 0.002 mmol, 0.01 eq) are stirred at 60° C. during 24 hours,when the solvent is evaporated. Flash column chromatography (CH₂Cl₂/MeOH95:5 to CH₂Cl₂/MeOH 9:1) affords the product as an light yellow solid.MS (LC-MS): 627 [M+H]⁺; R_(f) (CH₂Cl₂/MeOH 9:1): 0.25.

f)(2S,4S,5S,7S)-5-Amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl-8-methyl-nonanoicacid (1-hydroxymethyl-cyclopropylmethyl)-amide

At 5° C. 4N HCl/dioxane (0.97 ml) is added to((1S,2S,4S)-4-Cyclopropylcarbamoyl-1-{(S-2-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-3-methyl-butyl}-2-hydroxy-5-methyl-hexyl)-carbamicacid tert-butyl ester (89 mg, 0.14 mmol, 1.0 eq) in dioxane (0.8 ml).The resulting solution is stirred at 5° C. for 1 h whereupon it islyophilised. Flash column chromatography (CH₂Cl₂/MeOH(10% NH40H) 95:5 toCH₂Cl₂/MeOH(10% NH4OH) 9:1) affords the product as a light yellow solid.MS (LC-MS): 527.1[M+H]⁺; R_(f) (CH₂Cl₂/MeOH(10% NH4OH) 9:1): 0.16minutes.

EXAMPLE 5(2S,4S,5S,7S)-5-Amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl-8-methyl-nonanoicacid (3-hydroxy-2,2-dimethyl-propyl)-amide

The title compound prepared in accordance with General Procedure (IV).

MS (LC-MS): 527.1 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (10% NH₃) (9:1)]: 0.16minutes.

EXAMPLE 6(2S,4S,5S,7S)-5-Amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl-8-methyl-nonanoicacid (3-hydroxy-2,2-dimethyl-propyl)-amide

The title compound prepared in accordance General Procedure (IV).

MS (LC-MS): 606.1 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.16 minutes.

EXAMPLE 7 Cyclopropanecarboxylic acid[1-({(2S,4S,5S,7S)-5-amino-7-[4-fluoro-3-(3-methoxy-propoxy)-benzyl]-4-hydroxy-2-isopropyl-8-methyl-nonanoylamino}-methyl-cyclopropyl]-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 590.1 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (10% NH₃) (9:1)]: 0.16minutes.

EXAMPLE 8(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-methoxymethyl-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 551 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1): 0.16 minutes.

EXAMPLE 9(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-hydroxymethyl-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 537 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1): 0.15 minutes.

EXAMPLE 10(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2-fluoro-ethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 499.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.63 minutes.

EXAMPLE 11(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2,2-difluoro-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 518.1 [M+]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow. 1.5mL/min.): 4.75 minutes.

EXAMPLE 12(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2,2,2-trifluoro-ethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 535.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.9 minutes.

EXAMPLE 13(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid cyclopropylmethyl-amide

The title compound prepared in accordance with General Procedure (III).

MS (LC-MS): 508.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.91 minutes.

EXAMPLE 14(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-cyclopropyl-1-methyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 536.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.21 minutes.

EXAMPLE 15(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-1-cyclopropyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 522.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.95 minutes.

EXAMPLE 16(2S,4S,5S,7S)-5-Amino-4hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((S)-1-cyclopropyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 522.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.93 minutes.

EXAMPLE 17(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2,2-dimethyl-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 536.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.81 minutes.

EXAMPLE 18(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid[(1R,3S)-2,2-dimethyl-3-(2-methyl-propenyl)-cyclopropylmethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MD): 590.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.70 minutes.

EXAMPLE 19(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-1-cyclobutyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 536/1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.12 minutes.

EXAMPLE 20(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((S)-1-cyclobutyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 536.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.15 minutes.

EXAMPLE 21(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid cyclopentylmethyl-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 535.4 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.15 minutes.

EXAMPLE 22(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((S)-1-cyclopentyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.25 minutes.

EXAMPLE 23(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-1-cyclopentyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.24 minutes.

EXAMPLE 24(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-2,2-dimethyl-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.) 5.27 minutes.

EXAMPLE 25(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((S)-2,2-dimethyl-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.25 minutes.

EXAMPLE 26(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-methyl-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 535.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.08 minutes.

EXAMPLE 27(2S,4S,5S,7S)-5-amino-N-((1-fluorocyclopentyl)methyl)-4-hydroxy-2isopropyl-7-(4-methoxy-3-(3-methoxypropoxy)-benzyl)-8-methylnonanamide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 554 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.42 minutes.

EXAMPLE 28(2S,4S,5S,7S)-5-Amino4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid cyclohexylmethyl-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 549.3 [M]⁺; t_(R) (HPLC, C8 column, 595% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 3.87 minutes.

EXAMPLE 29(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((S)-1-cyclohexyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 564.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.36 minutes.

EXAMPLE 30(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-1-cyclohexyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 564.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.) 5.38 minutes.

EXAMPLE 31(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid cycloheptylmethyl-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 563.2 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.62 minutes.

EXAMPLE 32(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 590.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.) 5.71 minutes.

EXAMPLE 331-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopropanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 566.0 [M+H]⁺; t_(R) (HPLC, C8 column, 20-95% CH₃CN/H₂O/3.5minutes, 95% CH₃CN/1 minute, flow: 0.8 mL/min.): 2.44 minutes.

EXAMPLE 341-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-methyl)-cyclobutanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 580.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.11 minutes.

EXAMPLE 351-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclopentanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 580.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.02 minutes.

EXAMPLE 361-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-cyclopentanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 594.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.19 minutes.

EXAMPLE 371-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 594.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.13 minutes.

EXAMPLE 381-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl-cyclohexanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 608.0 [M+H]⁺; t_(R) (HPLC, C8 column, 20-95% CH₃CN/H₂O/3.5minutes, 95% CH₃CN/1 minute, flow: 0.8 mL/min.): 2.74 minutes.

EXAMPLE 39(S)-(2S,4S,5S,7S)-5-Amino4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexyl-aceticacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 608.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.) 5.26 minutes.

EXAMPLE 40(1S,3R)-3-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclopentanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 580.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.10 minutes.

EXAMPLE 41(1S,3R)-3-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino)-cyclopentanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 580.0 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.36 minutes.

EXAMPLE 424-((2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 594.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.08 minutes.

EXAMPLE 434-((2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylicacid methyl ester

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 594.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.01 minutes.

EXAMPLE 441-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl-cyclopentanecarboxylicacid

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 579.1 [M+H]⁺; t_(R) (HPLC, C8 column, 20-95% CH₃CN/H₂O/3.5minutes, 95% CH₃CN/1 minutes, flow: 0.8 mL/min.): 2.48 minutes.

EXAMPLE 45(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 453.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.41 minutes.

EXAMPLE 461-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopropanecarboxylicacid amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.05 minutes.

EXAMPLE 471-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclobutanecarboxylicacid amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 564.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.54 minutes.

EXAMPLE 481-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopentanecarboxylicacid amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 578.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1minute, flow: 0.5 mL/min.): 4.2 minutes.

EXAMPLE 491-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclohexanecarboxylicacid amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 592.2 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.02 minutes.

EXAMPLE 501-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclopentanecarboxylicacid amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 564.2 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min): 4.66 minutes.

EXAMPLE 512-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-C3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclopentanecarboxylicacid amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 564.3 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.3 minutes.

EXAMPLE 522-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-)-3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylicacid amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 578.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.84 minutes.

EXAMPLE 531-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopentanecarboxylicacid methylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 592.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.51 minutes.

EXAMPLE 54(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-formylamino-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 551 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.41 minutes.

EXAMPLE 55(2S14S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-acetylamino-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 565.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.46 minutes.

EXAMPLE 56(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-formylamino-cyclopentylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 579.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.7 minutes.

EXAMPLE 57(2S,4S,5S,7S)-5-Amino-4-hydroxy-2:isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-acetylamino-cyclopentylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 592.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.68 minutes.

EXAMPLE 58(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [1-(2,2-dimethyl-propionylamino)-cyclopentylmethyl]-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 634.2 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.18 minutes.

EXAMPLE 59(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid {1-[(2,2-dimethyl-propionylamino)-methyl]-cyclopentyl}-amide

The title prepared in accordance with General Procedure (II).

MS (LC-MS): 635.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.34 minutes.

EXAMPLE 60 Cyclopropanecarboxylic acid[1-({(2S,4S,5S,7S)-5-amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopentyl]-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.18 minutes.

EXAMPLE 61[1-({(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopropyl]-carbamicacid tert-butyl ester

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 623.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.22 minutes.

EXAMPLE 62[1-({(2S,4S,5S,7S)-5-Amino4-hydroxy-2-isopropyl-7-[4-methoxy-3-3methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-methyl)-cyclopentyl]-carbamicacid tert-butyl ester

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 650.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.43 minutes.

EXAMPLE 63(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-amino-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 523.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.33 minutes.

EXAMPLE 64(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-amino-cyclopentylmethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]³⁰ ; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.31 minutes.

EXAMPLE 65(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (4-amino-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.18 minutes.

EXAMPLE 66(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (4-amino-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 550.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.14 minutes.

EXAMPLE 67(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-dimethylamino-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 551.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.36 minutes.

EXAMPLE 68(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-dimethylamino-cyclopentylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 578.2 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.29 minutes.

EXAMPLE 69(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-methoxymethyl-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 565.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.11 minutes.

EXAMPLE 70(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-methoxy-cyclopentylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 566 [M+H]⁺; t^(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.01 minutes.

EXAMPLE 71(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1S,2S)-2-benzyloxy-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 628.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.38 minutes.

EXAMPLE 72(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1R,2R)-2-benzyloxy-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 628.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.42 minutes.

EXAMPLE 73(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (4-methoxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 565.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.59 minutes.

EXAMPLE 74(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (4-methoxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 565.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.67 minutes.

EXAMPLE 75(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1S,2S)-2-benzyloxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 641.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 6.10 minutes.

EXAMPLE 76(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1R,2R)-2-benzyloxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 641.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 6.00 minutes.

EXAMPLE 77(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-hydroxy-cyclopropylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 523.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.52 minutes.

EXAMPLE 78(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1R,2R)-2-hydroxy-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 538.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.74 minutes.

EXAMPLE 79(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1S,2S)-2-hydroxy-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 537.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.37 minutes.

EXAMPLE 80(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-hydroxymethyl-cyclopentyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 551.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.77 minutes.

EXAMPLE 81(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-hydroxy-cyclopentylmethyl)-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 552 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.72 minutes.

EXAMPLE 82(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1R,2R)-2-hydroxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 551.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.62 minutes.

EXAMPLE 83(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1S,2S)-2-hydroxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 551.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.41 minutes.

EXAMPLE 84(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (4-hydroxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 551.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.61 minutes.

EXAMPLE 85(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (4-hydroxy-cyclohexyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 552.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.81 minutes.

EXAMPLE 86(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-hydroxy-cyclohexylmethyl)-amide

The title compound prepared in accordance with General Procedure (III).

MS (LC-MS): 565.2 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.07 minutes.

EXAMPLE 87(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-1-phenyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 558.3 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.63 minutes.

EXAMPLE 88(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((S)-1-phenyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 558.3 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.69 minutes.

EXAMPLE 89 (2S,4S,5S,7S)-5-Amino4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-methyl-1-phenyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 572.0 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 3.85 minutes.

EXAMPLE 90(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (naphthalen-1-ylmethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 594.5 [M+H]⁺; R_(f) [CH₂Cl₂: MeOH (9:1)]: 0.21 minutes.

EXAMPLE 91(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid indan-2-ylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 569.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mLlmin.): 5.16 minutes.

EXAMPLE 92(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-methyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 558.3 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.17 minutes.

EXAMPLE 93(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-methyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 558.3 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.28 minutes.

EXAMPLE 94(2S,4S,5S,7S))-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-methyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 558.3 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 3.76 minutes.

EXAMPLE 95(2S,4$,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-1-p-tolyl-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 571.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.):

EXAMPLE 96(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((S)-1-p-tolyl-ethyl)-amide

The title prepared in accordance with General Procedure (I).

MS (LC-MS): 571.2 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.):

EXAMPLE 97(2S,4S,5S,7S))-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-isopropyl-benzylamide

The title prepared in accordance with General Procedure (I).

MS (LC-MS): 586.3 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mLlmin.): 4.26 minutes.

EXAMPLE 98(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-methoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 573.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.15 minutes.

EXAMPLE 99(2S,4S,5S,7S))-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-methoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 573.3 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.17 minutes.

EXAMPLE 100(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4methoxy-benzylamide

The title prepared in accordance with General Procedure (I).

MS (LC-MS); 573.3 [M+H]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.14 minutes.

EXAMPLE 101(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [(S)-1-(3-methoxy-phenyl)-ethyl]-epared in accordance with GeneralProcedure (I).

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 587.2 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.: 5.10 minutes.

EXAMPLE 102(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [(R)-1-(3-methoxy-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 587.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.10 minutes.

EXAMPLE 103(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [(S)-1-(4-methoxy-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 587.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.07 minutes.

EXAMPLE 104(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [(R)-1-(4-methoxy-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 587.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mLlmin.): 5.09 minutes.

EXAMPLE 105(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-methylsulfanyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 589.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.10 minutes.

EXAMPLE 106(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-methylsulfanyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 589.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.12 minutes.

EXAMPLE 107(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2,5-dimethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 603.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.13 minutes.

EXAMPLE 108(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2,3-dimethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 603.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.03 minutes.

EXAMPLE 109(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2,4-dimethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 603.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.23 minutes.

EXAMPLE 110(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3,4-dimethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 603.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.18 minutes.

EXAMPLE 111(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2,6-dimethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 603.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.24 minutes.

EXAMPLE 112(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3,5-dimethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 603.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.04 minutes.

EXAMPLE 113(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-trifluoromethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 627.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)): 0.31 minutes.

EXAMPLE 114(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-trifluoromethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 627.2 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.17 minutes.

EXAMPLE 115(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-trifluoromethoxy-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 627.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.26 minutes.

EXAMPLE 116(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-fluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 561.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.03 minutes.

EXAMPLE 117(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-fluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 561.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.09 minutes.

EXAMPLE 118(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-fluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 561.3 [M+H]⁺; t_(R) (HPLC, C18 column, 10100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.08 minutes.

EXAMPLE 119(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 575.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.11 minutes.

EXAMPLE 120(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [(S)-1-(4-fluoro-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 575.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.09 minutes.

EXAMPLE 121(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-chloro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 577.3 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.15 minutes.

EXAMPLE 122(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-chloro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 577.3 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.18 minutes.

EXAMPLE 123(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-chloro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 577.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.14 minutes.

EXAMPLE 124(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2,5-difluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 579.1 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.13 minutes.

EXAMPLE 125(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2,4-difluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 579.1 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.07 minutes.

EXAMPLE 126(2S,4S,5S,75)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2,6-difluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 579.0 [M]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 4.63 minutes.

EXAMPLE 127(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3,4-difluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LG-MS): 579.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.11 minutes.

EXAMPLE 128(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3,5-difluoro-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 579.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.12 minutes.

EXAMPLE 129(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-trifluoromethyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 611.1 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.43 minutes.

EXAMPLE 130(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3trifluoromethyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 611.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.59 minutes.

EXAMPLE 131(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-trifluoromethyl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 611.0 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min ): 5.43 minutes.

EXAMPLE 132(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-cyano-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 568.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.25 minutes.

EXAMPLE 133(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-dimethylamino-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 586.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.26 minutes.

EXAMPLE 134(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amide The title compoundprepared in accordance with General Procedure (I).

MS (LC-MS): 601.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.25 minutes.

EXAMPLE 135(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2,3-dihydro-benzo[1,4]dioxin-5-ylmethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 601.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.07 minutes.

EXAMPLE 136(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylmethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 615.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.07 minutes.

EXAMPLE 137(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2,3-dihydro-benzofuran-5-ylmethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 585.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.07 minutes.

EXAMPLE 138(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (benzofuran-4-ylmethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 583.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.11 minutes.

EXAMPLE 139(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-piperidin-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 626.4 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.58 minutes.

EXAMPLE 140(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-piperidin-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 628.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.35 minutes.

EXAMPLE 141(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-piperidin-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 626.4 [M]⁺; R_(f) (CH₂Cl₂:MeOH (9:1)]: 0.35 minutes.

EXAMPLE 142(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-morpholin-4-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 628.4 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.58 minutes.

EXAMPLE 143(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-morpholin4yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 628.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.61 minutes.

EXAMPLE 144(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-morpholin-4-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 628.4 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.55 minutes.

EXAMPLE 145(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 2-pyrrolidin-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 612.4 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.46 minutes.

EXAMPLE 146(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-pyrrolidin-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 612.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.66 minutes.

EXAMPLE 147(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-pyrrolidin-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 612.4 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 4.37 minutes.

EXAMPLE 148(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 3-pyrrol-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 608.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.37 minutes.

EXAMPLE 149(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-pyrrol-1-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 608.3 [M]⁺; R_(f) [CH₂Cl₂:MeOH (9:1)]: 0.35 minutes.

EXAMPLE 150(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid 4-thiophen-3-yl-benzylamide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 625.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.45 minutes.

EXAMPLE 151(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid phenethyl-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 557.1 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.18 minutes.

EXAMPLE 152(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [1-methyl-1-(1-phenyl-cyclopropyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (II).

MS (LC-MS): 611.1 [M+H]⁺; t_(R) (HPLC, C8 column, 5-95% CH₃CN/H₂O/6.5minutes, 95% CH₃CN/H₂O/1 minute, flow: 0.5 mL/min.): 5.6 minutes.

EXAMPLE 153(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [2-(2-fluoro-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 575.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.12 minutes.

EXAMPLE 154(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [2-(3-fluoro-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 575.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.11 minutes.

EXAMPLE 155(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [2-(4-fluoro-phenyl)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 575.0 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.06 minutes.

EXAMPLE 156(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (2-phenoxy-ethyl)-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 573.3 [M]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.08 minutes.

EXAMPLE 157(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid [2-(4-methoxy-phenoxy)-ethyl]-amide

The title compound prepared in accordance with General Procedure (I).

MS (LC-MS): 603.1 [M+H]⁺; t_(R) (HPLC, C18 column, 10-100% CH₃CN/H₂O/5minutes, 100% CH₃CN/3 minutes, 100-10% CH₃CN/H₂O/3 minutes, flow: 1.5mL/min.): 5.09 minutes.

EXAMPLE 158 Gelatin solution

A sterile-filtered aqueous solution, containing 20% cyclodextrins assolubiliser, of one of the compounds of formula (I), mentioned in thepreceding Examples, as active ingredient, is so mixed, with theapplication of heat and under aseptic conditions, with a sterile gelatinsolution containing phenol as preservative, that 1.0 mL of solution hasthe following composition:

active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg dist. watercontaining 20% cyclodextrins as solubiliser 1.0 mL

EXAMPLE 159 Sterile Dry Substance for Injection

Five (5) mg of one of the compounds of formula (I), mentioned in thepreceding Examples, as active ingredient, are dissolved in 1 mL of anaqueous solution containing 20 mg of mannitol and 20% cyclodextrins assolubiliser. The solution is sterile-filtered and, under asepticconditions, introduced into a 2 mL ampoule, deep-frozen and lyophilised.Before being used, the lyophilisate is dissolved in 1 mL of distilledwater or 1 mL of physiological saline. The solution is administeredintramuscularly or intravenously. The formulation can also be filledinto double-chamber disposable syringes.

EXAMPLE 160 Nasal Spray

Five hundred (500) mg of finely ground (<5.0 gm) powder of one of thecompounds of formula (I), mentioned in the preceding Examples, aresuspended as active ingredient in a mixture of 3.5 mL of “Myglyol 8 12”and 0.08 g of benzyl alcohol. The suspension is introduced into acontainer having a metering valve. Five (5.0) g of “Freon 12” areintroduced under pressure through the valve into the container. The“Freon” is dissolved in the Myglyolbenzyl alcohol mixture by shaking.The spray container contains approximately 100 single doses which can beadministered individually.

EXAMPLE 161 Film-coated Tablets

The following constituents are processed for the preparation of 10 000tablets each containing 100 mg of active ingredient:

active ingredient 1000 g  corn starch 680 g colloidal silicic acid 200 gmagnesium stearate  20 g stearic acid  50 g sodium carboxymethyl starch250 g water quantum satis

A mixture of one of the compounds of formula (I), mentioned in thepreceding Examples, as active ingredient, 50 g of corn starch and thecolloidal silicic acid is processed into a moist mass with starch pasteprepared from 250 g of corn starch and 2.2 kg of demineralised water.The mass is forced through a sieve having a mesh size of 3 mm and driedat 45° C. for 30 minutes in a fluidised bed drier. The dried granulesare pressed through a sieve having a mesh size of 1 ram, mixed with apreviously sieved mixture (1 mm sieve) of 330 g of corn starch, themagnesium stearate, the stearic acid and the sodium carboxymethyl starchand compressed to form slightly biconvex tablets.

Although the present invention has been described in considerable detailwith reference to certain preferred versions thereof, other versions arepossible without departing from the spirit and scope of the preferredversions contained herein. All references and Patents (U.S. and others)referred to herein are hereby incorporated by reference in theirentirety as if set forth in full herein.

1. A δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide compound of formula(I)

wherein R¹ is hydrogen, halogen, optionally halogenated alkyl,cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy, loweralkoxy-lower alkoxy or free or esterified or amidated carboxy-loweralkoxy or lower alkyl; R² is hydrogen, halogen, optionally halogenatedlower alkyl, hydroxy, cycloalkyl, cycloalkoxy, optionally halogenatedlower alkoxy-lower alkyl, optionally substituted lower alkoxy-loweralkyl, cycloalkoxy-lower alkyl; optionally lower alkanoylated,halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower alkyl thatis unsubstituted or substituted by lower alkyl, by lower alkanoyl and/orby lower alkoxycarbonyl, optionally hydrogenated heteroaryl-lower alkyl,amino-lower alkoxy that is substituted by lower alkyl, by lower alkanoyland/or by lower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy, loweralkenyloxy, cycloalkoxy-lower alkoxy, lower alkoxy-lower alkoxy, loweralkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-loweralkenyloxy, lower alkenyloxy-lower alkyl, lower alkanoyl lower alkoxy,optionally S-oxidised lower alkylthio-lower alkoxy, loweralkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, aryl-lower alkyl,aryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy,optionally hydrogenated heteroaryl-lower alkyl, cyano-lower alkoxy,cyano-lower alkyl, free or esterified or amidated carboxy-lower alkoxyor free or esterified or amidated carboxy-lower alkyl; R³ and R⁴ areindependently hydrogen, halogen, optionally halogenated lower alkyl,hydroxy, optionally halogenated lower alkoxy or cycloalkoxy, loweralkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy-lower alkyl,optionally S-oxidised lower alkylthio-lower alkyl, optionallyhydrogenated heteroarylthio-lower alkyl, optionally hydrogenatedheteroaryl-lower alkyl; amino-lower alkyl that is unsubstituted orN-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-loweralkanesulfonylated or N,N-disubstituted by lower alkylene, byunsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-loweralkylene, by oxa-lower alkylene or by optionally S-oxidised thia-loweralkylene, cyano-lower alkyl, free or esterified or amidatedcarboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy,cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy,hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated loweralkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally hydrogenatedheteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted orN-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-loweralkanesulfonylated or substituted by lower alkylene, by unsubstituted orN′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, byoxa-lower alkylene or by optionally S-oxidised thia-lower alkylene,cyano-lower alkoxy or free or esterified or amidated carboxy-loweralkoxy; or R⁴ together with R₃ is lower alkeneoxy, lower alkylenedioxyor a fused-on aryl, optionally hydrogenated heteroaryl or cycloalkylring; X is methylene, hydroxymethylene, oxygen, optionally lower alkylsubstituted nitrogen, optionally oxidized sulfur; R⁵ is lower alkyl orcycloalkyl; R⁶ is hydrogen, lower alkyl, hydroxy, alkoxy or halogen; R⁷is unsubstituted or N-mono- or N,N-di-lower alkylated or N-loweralkanoylated amino; R⁸ is lower alkyl, lower alkenyl, cycloalkyl oraryl-lower alkyl; R⁹ is optionally substituted cycloalkyl; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 wherein R⁹ is optionally substituted cycloalkyl (alkyl, OH,alkoxy, alkoxy-alkyl, halogens); or a pharmaceutically acceptable saltthereof.
 3. The compound according to claim 2 wherein R¹ and R⁴ arehydrogen; R² is lower alkoxy-lower alkoxy; R³ is halogen or mono, di ortri-halo-substituted alkyl; or a pharmaceutically acceptable saltthereof.
 4. The compound according to claim 3 wherein the halogen/halois fluorine or chlorine; or a pharmaceutically acceptable salt thereof.5. The compound according to claim 4 wherein R³ is fluorine ortrifluoromethyl; or a pharmaceutically acceptable salt thereof.
 6. Thecompound according to claim 5 wherein R² is in the meta position and R³is in the para position; or a pharmaceutically acceptable salt thereof.7. The compound according to claim 5 wherein R³ is in the orthoposition; or a pharmaceutically acceptable salt thereof.
 8. The compoundaccording to claim 5 wherein R³ is in the meta position; or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 2 wherein R² is in the meta position and is lower alkoxy-loweralkoxy optionally substituted by halogen(s); or a pharmaceuticallyacceptable salt thereof.
 10. The δ-amino-γ-hydroxy-ω-aryl-alkanoic acidamide compound according to claim 1 having formula (Ia)

wherein R¹ is hydrogen, halogen, optionally halogenated alkyl,cycloalkyl, hydroxy, optionally halogenated alkoxy, cycloalkoxy, loweralkoxy-lower alkoxy or free or esterified or amidated carboxy-loweralkoxy or lower alkyl; R² is hydrogen, halogen, optionally halogenatedlower alkyl, hydroxy, cycloalkyl, cycloalkoxy, optionally halogenatedlower alkoxy-lower alkyl, optionally substituted lower alkoxy-loweralkoxy, cycloalkoxy-lower alkyl; optionally lower alkanoylated,halogenated or sulfonylated hydroxy-lower alkoxy; amino-lower alkyl thatis unsubstituted or substituted by lower alkyl, by lower alkanoyl and/orby lower alkoxycarbonyl; optionally hydrogenated heteroaryl-lower alkyl;amino-lower alkoxy that is substituted by lower alkyl, by lower alkanoyland/or by lower alkoxycarbonyl; oxo-lower alkoxy, lower alkoxy,cycloalkoxy, lower alkenyloxy, cycloalkoxy-lower alkoxy, loweralkoxy-lower alkenyl, lower alkenyloxy-lower alkoxy, lower alkoxy-loweralkenyloxy, lower alkenyloxy-lower alkyl, lower alkanoyl-lower alkoxy,optionally S-oxidised lower alkylthio-lower alkoxy, loweralkylthio-(hydroxy)-lower alkoxy, aryl-lower alkoxy, aryl-lower alkyl,aryl-lower alkoxy, optionally hydrogenated heteroaryl-lower alkoxy,optionally hydrogenated hetero-aryl-lower alkyl, cyano-lower alkoxy,cyano-lower alkyl, free or esterified or amidated carboxy-lower alkoxyor free or esterified or amidated carboxy-lower alkyl; R³ and R⁴ areindependently hydrogen, halogen, optionally halogenated lower alkyl,hydroxy, optionally halogenated lower alkoxy or cycloalkoxy, loweralkoxy-lower alkyl, cycloalkoxy-lower alkyl, hydroxy-lower alkyl,optionally S-oxidised lower alkylthio-lower alkyl, optionallyhydrogenated heteroarylthio-lower alkyl, optionally hydrogenatedhetero-aryl-lower alkyl; amino-lower alkyl that is unsubstituted orN-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-loweralkanesulfonylated or N,N-disubstituted by lower alkylene, byunsubstituted or N′-lower alkylated or N′-lower alkanoylated aza-loweralkylene, by oxa-lower alkylene or by optionally S-oxidised thia-loweralkylene; cyano-lower alkyl, free or esterified or amidatedcarboxy-lower alkyl, cycloalkyl, aryl, hydroxy, lower alkoxy,cycloalkoxy, lower alkoxy-lower alkoxy, cycloalkoxy-lower alkoxy,hydroxy-lower alkoxy, aryl-lower alkoxy, optionally halogenated loweralkoxy, optionally S-oxidised lower alkylthio-lower alkoxy, optionallyhydrogenated heteroaryl-lower alkoxy, optionally hydrogenatedheteroarylthio-lower alkoxy; amino-lower alkoxy that is unsubstituted orN-mono- or N,N-di-lower alkylated, N-lower alkanoylated or N-loweralkanesulfonylated or substituted by lower alkylene, by unsubstituted orN′-lower alkylated or N′-lower alkanoylated aza-lower alkylene, byoxalower alkylene or by optionally S-oxidised thia-lower alkylene;cyano-lower alkoxy or free or esterified or amidated carboxy-loweralkoxy; or R⁴ together with R₃ is lower alkeneoxy, alkylenedioxy or afused-on aryl, optionally hydrogenated heteroaryl or cycloalkyl ring; Xis methylene, hydroxymethylene, oxygen, optionally lower alkylsubstituted nitrogen or optionally oxidized sulfur; R⁵ is lower alkyl orcycloalkyl; R⁶ is hydrogen, lower alkyl, hydroxy, alkoxy or halogen; R⁷is unsubstituted or N-mono- or N,N-di-lower alkylated or N-loweralkanoylated amino; R⁸ is lower alkyl, lower alkenyl, cycloalkyl oraryl-lower alkyl; R⁹ is optionally substituted cycloalkyl; or apharmaceutically acceptable salt thereof.
 11. The compound according toclaim 10 wherein R⁹ is cycloalkyl substituted with alkyl, hydroxy,alkoxy, alkoxy-alkoxy or halogens; or a pharmaceutically acceptable saltthereof.
 12. The compound according to claim 10 wherein R⁹ is cycloalkylsubstituted by 1 to 3 substituents selected from the group consisting ofalkenyl, alkynyl, halo, hydroxy, alkoxy, alkoxy-alkoxy, alkylthio,arylthio, aryl-alkoxy, carbamoyl, sulfamoyl, sulfonyl, optionallysubstituted amino, cyano, carboxy, alkoxycarbonyl, aryl, aryloxy,heterocyclyl or alkyl optionally substituted by amino, halo, hydroxy,alkoxy, carboxy, alkoxycarbonyl, carbamoyl or heterocyclyl; or apharmaceutically acceptable salt thereof.
 13. The compound according toclaim 12 wherein R¹ is hydrogen; R² is C₁-C₄ alkoxy-C₁-C₄ alkoxy orC₁-C₄ alkoxy-C₁-C₄ alkyl; R³ is C₁-C₄ alkyl or C₁-C₄ alkoxy; R⁴ ishydrogen; X is methylene; R⁵ is lower alkyl; R⁶ is hydrogen; R⁷ isunsubstituted amino; R⁸ is branched C₃-C₄ alkyl; R⁹ is optionallysubstituted cycloalkyl; or a pharmaceutically acceptable salt thereof.14. The compound according to claim 13 wherein R² is 3-methoxypropyloxy;R³ is methoxy; R⁵ is isopropyl; R⁸ is isopropyl; or a pharmaceuticallyacceptable salt thereof.
 15. A pharmaceutical composition, comprising:the compound according to claim 1 and one or more pharmaceuticallyacceptable excipient(s).
 16. A compound named(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid (1-hydroxymethyl-cyclopentyl)-amide, or a pharmaceuticallyacceptable salt thereof.
 17. A compound named1-{(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoylamino}-cyclohexanecarboxylicacid methyl ester, or a pharmaceutically acceptable salt thereof.
 18. Acompound named(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((1S,2S)-2-hydroxy-cyclopentyl)-amide, or a pharmaceuticallyacceptable salt thereof.
 19. A compound named(2S,4S,5S,7S)-5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxy-propoxy)-benzyl]-8-methyl-nonanoicacid ((R)-2,2-dimethyl-cyclopentyl)-amide, or a pharmaceuticallyacceptable salt thereof.